Professor of Pediatrics, Associate Program Director, Pediatric Endocrinology
Director, Pediatric Endocrine outpatient Services, University of California, San Francisco
https://profiles.ucsf.edu/stephen.rosenthal
Once a set of comparisons is made among a group of languages arthritis medication otc generic 4mg medrol with amex, identifying cognate and noncognate words for a large number of different meanings (a meaning being what a word refers to) rheumatoid arthritis ulnar nerve medrol 16mg on line, the resulting data can be used along with formal methods to infer the phylogenetic tree arthritis pain when it rains cheap 4mg medrol visa. A variety of different methods are commonly used to infer trees arthritis medication breastfeeding 16mg medrol with amex, including parsimony arthritis burning discount medrol 16 mg without prescription, distance arthritis friendly diet medrol 4mg low cost, and likelihood methods, and these are broadly similar whether applied to genetic or linguistic data. Parsimony methods seek a tree that minimizes the number of evolutionary events along its branches. Thus, parsimony methods would favor a tree that put English with German, and French with Italian or Spanish, over one, for example, that showed German as more closely related to Spanish than to English. To put German next to Spanish would suggest that the word water or wasser had somehow evolved twice. Distance 792 Evolution and Modern Society 140 20 18 16 14 12 A 120 100 B Count 10 8 6 4 2 0 0 0. Half-life estimates, t50 (B) Counts of the word half-life estimates as derived from the rates of lexical replacement for the same 200 words. The half-life measures the expected amount of time before a word has a 50 percent chance of being replaced by a new, unrelated word. The average half-life is 5300 years, with a median of 2500 years, and ranges from 750 to a theoretical value of 76,000. Likelihood methods use formal statistical models to estimate the probability of changes in words through time. A tree is constructed that makes the observed set of changes most probable, given the model of evolution. Trees such as the one depicted in figure 2 have now also been produced for the Austronesian languages, the Bantu languages of Africa, the Arawak languages of South America, the Semitic languages, the Uralic languages of Northern Europe, and some Melanesian languages, and this is an important and growing area of the field of evolutionary linguistics. The existence of sets of languages that comprise families of related languages shows that at least some elements of language evolve slowly enough to preserve signals of their ancestry dating back thousands of years. For example, linguists recognize that the word for two of something is probably derived in all IndoEuropean languages from a shared ancestral sound that has been conserved for many thousands of years. Thus, in Spanish the word is dos, it is twee in Dutch, deux in French, due (doo-ay) in Italian, dois in Portuguese, duo (dy in Greek, di in Albanian, and do in Hindi and ґo) Punjabi; Julius Caesar would have said duo. This conservation leads to the proposal that the original or protoIndo-European word that was spoken perhaps 9000 years ago was also "two"-as it sounds-and indeed, some scholars suggest it was duwo or duoh. A handful of other words, including three, five, who, I, and you, are also highly conserved. For example, the English word three is tre in Swedish and Danish, drei in German, tre in Italian and tres in Spanish, tria in Greek, teen in Hindi and tin in Panjabi, and tri in Czech, leading to the suggestion that the proto-Indo-European word for three might have been trei. These conserved words are closely followed by pronouns such as he and she, and by the what, where, and why words, all of which often show a striking degree of similarity among many IndoEuropean languages. Other words, however, can vary considerably across these same languages, meaning that they have evolved or changed at far higher rates. The English word bird, for example, is vogel in German, oiseau in French, and pajaro in Spanish. When long lists of words are studied for their frequency of change among the languages of a language family such as Indo-European, it is possible to derive estimates of their rates of change using statistical methods. It turns out that most words can be expected to last somewhere around 1500 to 2500 years, with some lasting far longer and others for shorter amounts of time (figure 3). Linguistics and Human Language this approach shows that some words might be expected to last more than 10,000 years. The linguist Merritt Ruhlen has even proposed a list of "global etymologies" that he thinks are signals leftover from the last common ancestor to all human languages, or our mother tongue. The mere existence of a mother tongue is controversial, and many linguists dispute the list, but Ruhlen cites evidence that traces of these words are found in many language families from all over the world. Given all the opportunities for neighboring language groups to borrow words from one another, and all the ways that words can change, language changes far more slowly that we might expect; that is, from the standpoint of effective communication, words do not need to last much more than around three generations-the time span covered in a typical population of speakers. If they changed faster than that, then we might not be able to talk to our grandparents. But most words last somewhere around 1500 to 2500 years, so why is there such fidelity in language? One answer comes from thinking of elements of languages as "replicators" that must adapt to the environment of the human mind. It follows that those words that are easiest to remember and say will tend to be those retained. We can see the current competition for space in our mind in common words like sofa and couch, or living room, sitting room, reception room, and parlor. There are no simple answers, but precisely because there is seldom any necessary connection between a sound and its meaning, the competition often focuses on characteristics of the sounds themselves, and thus we can expect the competition to be more intense the more often a word is used. There is a huge disparity in how often different words get used; in fact, so great is the disparity that about 25 percent of all human speech is made up from a mere 25 words. Not surprisingly, perhaps, the words used most frequently have common characteristics: they are short, often monosyllabic, distinct, and easy to pronounce. It is not that these frequently used words are somehow more important, but that they might be stable over long periods because they have become so highly adapted Our native language is, perhaps, one of our most intimate traits, being the voice of the "I" or "me" that defines our conscious self. It is the language of our thinking, and it is the code in which many of our memories are stored. Thus it is not surprising that one of the greatest personal losses a people can suffer is the loss of their native language. And yet, currently somewhere about 15 to 30 languages go extinct every year as small traditional societies dwindle in numbers or get overwhelmed by larger neighbors, and younger generations choose to learn the languages of larger and politically dominant societies. Whatever the true numbers of languages going extinct, the loss of languages greatly exceeds the loss of biological species as a proportion of their respective totals. This raises the question of which language will win if ever a single language should succeed all others on earth. Currently three languages are spoken by a far greater number of people than any of their competitors. It is not that these languages are better than their rivals; it is that they have had the fortune of being linked to demographically prosperous cultures. Still, English itself might be transformed as it is bombarded by the influences of such large numbers of nonnative English speakers who bring along their accents, grammar, and words to English when they speak it. This ability of English to take in so-called foreign words has been the key to its adaptability for at least the millennium since the Norman conquest of the English in 1066 brought an influx of Norman French vocabulary. Just as words must adapt to be competitive in the struggle to gain access to our mind, languages have to adapt as a whole to remain useful to their speakers, and those that do so will be the survivors. Self-appointed human "minders" in the form of reactionary grammarians, sticklers for spelling, or those who deliberately try to exclude some words and phrases will succeed in controlling the rate at which their languages naturally change, but in doing so they might consign these languages to the backwaters of international communication. This might already be happening to French and German, as both governments have ministries 794 Evolution and Modern Society origin. This study used language phylogeny to test a historical hypothesis for the timing of the origin of Indo-European languages. Provides a general overview of language evolution, including a description of methods of phylogenetic inference, and statistical studies of how languages evolve. One chapter of this book presents many of the arguments given here about why language evolved. Frequency of word use predicts rates of lexical evolution throughout Indo-European history. If communication is important, languages will never change at rates that imperil the very reason for which they exist. Reconstruction of human evolution: Bringing together genetic, archaeological, and linguistic data. What cultural evolution is not Memetics Cultural evolution Nonhuman animal cultural evolution Defining culture For most of the twentieth century, evolutionary theory focused on phenotypic variation underpinned by inherited genetic variation. Any comprehensive account of the evolution of the human species, and some animal species, must acknowledge that this is at best a simplification of the forces affecting change and stasis in these lineages. Habits, know-how, and technology-what we might consider cultural traits-can also contribute to survival and reproduction. Moreover, these traits are often maintained, in our own species at the very least, by learning from others- that is, they are inherited nongenetically. Further, these traits often show patterns of cumulative improvement as discoveries made in one generation are built on and modified. There also exist subgroups with distinct traits, again often generated and maintained through learning. Theories of cultural evolution start from the observation that humans, and possibly other species, display these important prerequisites for evolution-variation and inheritance of cultural traits-and attempt to build rigorous accounts of cultural change based on this observation. How exactly these accounts should be fashioned, what relationship cultural evolution should have with organic evolution, and how culture itself should be conceived remain open questions. A process of change in the traits mani- tion, sometimes also used to refer to transmission from any nonparent. A cultural entity, intended to be analogous to a gene, capable of being replicated and transmitted between individuals. An entity capable of being replicated and capable of influencing its own chances of being replicated through its effects on the world. Not all evolutionary approaches that seek to account for cultural phenomena are theories of cultural evolution. Evolutionary psychologists acknowledge that changes in cultural environments can affect the behavioral outputs of cognitive adaptations, but they tend to downplay the role of nongenetic inheritance. As a consequence, they also tend to be skeptical of the thought that cultural change may affect and underpin the generation of cognitive adaptations themselves. Nonetheless, cultural inheritance and genetic inheritance are processes that may affect each other in important ways. Cultural changes bring about alterations to the environment, which in turn affect how genes act in development and what selection pressures act on genes. For example, dairy farming, thought to have developed somewhere between 6000 and 8000 years ago, appears to have created a selective environment that facilitated the proliferation of lactose tolerance in those populations where it was practiced. Far from removing humans from the evolutionary fray, our cultural environments may exert 796 Evolution and Modern Society meme may replicate itself is thought to be dependent on the same factors that determine the rate at which a gene may replicate itself-namely, its effects on the organism it inhabits and on the local environment (partly constituted by the downstream effects of other memes) in which the organism finds itself. Critics of memetics put pressure on the claim that cultural inheritance is analogous to genetic inheritance. Such criticisms are as likely to originate from those sympathetic to the broad project of developing evolutionary approaches to culture as they are from those outside this project and doubtful of its merits. The remainder of this section outlines some of the key criticisms leveled against memetics. First, cultural items rarely behave like replicators, and imitation is often very error prone. If you see us dance the tango, and this inspires in you the desire to also dance the tango, we will almost certainly not dance exactly the same steps. Our dances will have been influenced by a wide variety of factors such as who taught us the dance and our own particular physiologies. A second and closely related criticism of memetics draws on the fact that while genetic replication allows us to trace a token copy of a gene back to a single parent, ideas are rarely copied from a single source in a way that allows us to trace clear lineages. Perhaps you learned the tango from several teachers, and your style has been influenced by watching expert dancers. Such an objection need not be fatal for theories of cultural evolution in general, as we shall see, but it does threaten the tight analogy memetics draws between ideas and genes. Third, memetics seems to demand that we be able to divide culture into discrete units. It is impossible to believe in the theory of relativity without understanding it, and one cannot understand it without holding many additional beliefs relating to physics. It is not at all clear that it makes sense to think that the theory of relativity can be isolated from the rest of physics as an individual meme. One might respond that we have delineated the meme incorrectly here, and those ideas to which the theory of relativity stands in logical relation all form a part of a single more inclusive meme. The worry, now, is that even if we "step back" selective pressures and thus may be implicated in the ongoing evolution of our physiological natures. These sorts of processes are captured by models of gene-culture coevolution that explore the ways in which cultural changes, adaptive or otherwise, can affect genetic evolution, and vice versa. The targets of explanation for evolutionary psychology and gene-culture coevolutionary accounts differ from those of theories of cultural evolution. The latter address cultural trends in their own right, rather than as outputs of cognitive adaptations or as selective environments for the natural selection of genes. Further, unlike evolutionary psychology, though in common with gene-culture coevolutionary accounts, theories of cultural evolution allow a significant amount of nongenetic, learning-based inheritance. The remainder of this chapter describes two distinct attempts to build a theory of cultural evolution from this starting point. One such approach is memetics, which has attracted considerable attention in the popular scientific literature. In standard biological models of evolution it is assumed that genes are the relevant replicators; genes make copies of themselves, and (so the story goes) this explains why offspring resemble their parents. For culture to evolve, memeticists argue that replicators-called memes-are once again required. Dawkins lists some exemplary memes: "tunes, ideas, catch-phrases, clothes fashions, ways of making pots or of building arches. Memetics proposes that ideas, skills, practices, and so on, are entities that can be understood to hop from mind to mind, making copies of themselves as they go. For example, you hear a song on the radio as you leave your house in the morning and you sing it at work that day. Her child hums the song in school the next day and passes it on to his classmates. The rate at which a Cultural Evolution and consider some broader group of theories, we cannot understand even them without further basic mathematical training, understanding of the operation of measuring apparatus, and so forth. A form of holism looms, according to which single memes will correspond to massive complexes of belief. Another matter of concern for memetics in particular, and theories of cultural evolution in general, stems from the fact that cultural transmission occurs both vertically and horizontally. Inheritance as understood in mainstream evolutionary biology involves vertical transmission, whereby genetic inheritance is taken to occur between parents and their offspring.
Even if some form of contraception is available there is likelihood of unwanted pregnancy since the most effective and practical contraceptives arthritis pain disability order 16 mg medrol overnight delivery, such as the birth control pill arthritis treatment knee joints order 4mg medrol fast delivery, the intrauterine device arthritis medication breastfeeding generic medrol 4 mg online, and the diaphragm can be obtained only on the prescription of a doctor whose services are denied to hundreds of thousands of poor arthritis suitable diet buy generic medrol 4mg. Moreover arthritis knee mri images order medrol 16 mg line, their use is medically contraindicated for certain patients arthritis in back pain generic medrol 4mg with amex, particularly those with a history of thromboembolic disease. Except for voluntary sterilization which many people will not use, even the most effective or highly effective methods have shortcomings either in terms of method failures or in terms of side effects or medical contraindications. In addition some of the methods are so difficult to practice regularly and correctly that they have little practical utility. Amicus Curiae Brief in Support of Jane Roe American Ethical Union, American Friends Service Committee, American Humanist Association, American Jewish Congress, Episcopal Diocese of New York, New York State Council of Churches, Union of American Hebrew Congregations, Unitarian Universalist Association, United Church of Christ, and Board of Christian Social Concerns of the United Methodist Church. It maintains that for the government to enforce policies based on the Catholic faith-that "the product of every conception is sacred"-would amount to an unconstitutional "establishment" of religion. Helen Buttenwieser (19051989) was a civic leader and one of the most prominent female attorneys in New York City. In addition to the nine religious organizations listed on the cover, the brief was also signed by the Planned Parenthood Association of Atlanta, Inc. They do advocate the right of an individual to be free from State interference in the conduct of his or her private life. The brief of the Amici stresses that the States may not unreasonably interfere with the constitutional right of an individual to determine the course of his or her own life and that the Georgia and Texas abortion laws constitute such an interference. The Georgia and Texas abortion laws unjustifiably restrict the reserved constitutional liberty of all persons to conduct their private lives without unwarranted governmental interference. The religious view that the product of every conception is sacred may not validly be urged by the States as a justification for limiting the exercise of constitutional liberties, for that would be an establishment of religion. The real basis of the claim of state interest in the foetus is a doctrinaire "moral" concern for the "potential of independent human existence. Reflective judges, scholars and commentators have perceived and deplored the fact that religious beliefs underlie the retention of abortion laws. No argument is needed to show that the police power cannot be employed in the service of sectarian moral views without violating the Establishment Clause of the First Amendment. Amicus Curiae Brief in Support of Jane Roe California Committee to Legalize Abortion; South Bay Chapter of the National Organization for Women; Zero Population Growth, Inc. The brief includes a graphic description of the physical burdens of pregnancy, an interesting counterpoint to the detailed portrait of prenatal development contained in the main Texas brief. Each of the organizations and individuals urges upon the Court the position that laws restricting or regulating abortion as a special procedure violate the Thirteenth Amendment by imposing involuntary servitude without due conviction for a crime and without the justification of serving any current national or public need. The Thirteenth Amendment to the Constitution provides: neither slavery nor involuntary servitude, except as a punishment for crime whereof the party shall have been duly convicted, shall exist within the united states, or any place subject to their jurisdiction. From the outset, the Amendment has been interpreted by this Court to apply to all persons without regard to race or class, and to guarantee universal freedom in the United States. It is the purpose of this brief to show that anti-abortion laws, which force an unwillingly pregnant woman to continue pregnancy to term, are a form of involuntary servitude without the justification of serving any current national or public need. They are performed for the benefit of the conceptus alone unless an interest of the pregnant woman is also served thereby, that is, unless the pregnant woman defines the pregnancy as wanted. During pregnancy, enlargement of the uterus within the abdominal cavity displaces and compresses the other abdominal contents including the heart, lungs and gastrointestinal tract. The resulting pressure has a direct effect on circulation of the blood and increase in venous pressure, sometimes leading to irreversible varicose veins and hemorrhoids and, with predictable frequency, to disabling thrombophlebitis. The gastrointestinal tract experiences functional interference causing constipation and displacement of the urinary tract, thus urinary tract infections occur in six to seven per cent of all pregnant women and such infections, in turn, lead to kidney infections. Tearing and overstretching of the muscles of the pelvic floor occurs frequently during delivery, causing extensive and irreparable damage to the pelvic organs and their supporting connections. During pregnancy estrogen levels exhibit severe increase, this phenomenon accounting for the symptoms of nausea and vomiting occurring in one-half or more of all pregnant women. Evacuation of the contents of the uterus results in immediate and dramatic relief of symptoms. Bodies of women who have died from this condition exhibit the symptoms of starvation, acidosis, dehydration and multiple vitamin deficiencies. The excess progesterone produced by the placenta causes fluid retention, increase in blood pressure, weight gain, irritability, lassitude, severe emotional tension, nervousness, inability to concentrate, and inability to sleep. At least 40 per cent of pregnant women have symptomatic edema, distorting the hands, face, ankles and feet. Thus anemia of pregnancy is high and almost all pregnant women, especially those having repeated pregnancies, require supplementary iron. Efforts to correct this condition may fail because many pregnant women cannot tolerate iron supplements. With such extensive effects, can pregnancy be considered as merely a "natural" state of being? Amici ask this Court to consider the lack of options open to the pregnant woman at the time of onset of her pregnancy. Any act of intercourse between a fertile man and woman constitutes some risk of conception, no matter what contraceptives are used. If 100,000 women who do not wish to become pregnant take the pill, three will probably die within the year and 1,000 will become pregnant. She is at some risk in using the most effective methods of contraception available. The frequency of coitus stated in the Kinsey Report is average behavior between married couples. If the woman wishes to remain free of pregnancy once her desired family size is reached, her only sure method of remaining so free of pregnancy is complete abstinence from sexual intercourse. A wife has no legal power to refuse to participate in the intimacies of married life. Indeed, if a married woman attempts to practice abstinence, the laws of most states treat her behavior as a denial of the marital right of the husband. Under present law, a married woman has two choices: she can attempt to refuse to fulfill the sexual obligations of the marriage and thus risk termination of her marriage; or she can participate in normal marital relations and risk unwanted pregnancy and childbirth. With a choice of either alternative, she risks the consequence of a legally imposed penalty. The women who bear children and the medical experts who assist them testify that pregnancy and childbearing are indeed labor. The fact that many women enter into such labor voluntarily and joyfully does not alter the fact that other women, under other circumstances, find childbearing too arduous, become pregnant through no choice of their own, and are then forced to complete the pregnancy to term by compulsion of state laws prohibiting voluntary abortion. It is the purpose of the Thirteenth Amendment to prohibit a relationship in which one person or entity limits the freedom of another person. Let us assume, for the time being, that the pregnant woman and the fetus she carries within her body have come before the law as equal "persons. At the present stage of medical knowledge and ability to control human incubation, the fetus cannot survive and develop into a separate self-sustaining person without contribution of the bodily force of the single female individual who carries that particular fetus within her body. Yet the laws prohibiting and regulating abortion, unlike all other laws in respect of persons, compel this pregnant woman to breathe, process food and donate blood for the sustenance of another human entity, either fully or partially developed. In no other instance does the law compel one individual to donate his/her bodily force to another individual. In no other instance does the law give another human-even a fully developed human-a right to life beyond that which the person himself can sustain. The law does not give a person in need of blood the right to receive blood from an unwilling donor; the conclusiveness of the law on this subject being so clearly recognized that it is difficult even to imagine testing such a principle in the courts. If the pregnant woman, as potential donor, and the fetus, as potential donee, come before the law as equal "persons," one may not command involuntary servitude of the other; and so the potential donor retains her sovereignty over her body and her right to refuse. Therefore, it follows that the fetus, a potential person, can have no greater right over a potential donor. A state cannot seriously contend today that restrictions on abortion are justified by an overriding state interest in increasing population. On the contrary, it is accepted government policy to limit family size and to encourage family planning. Anti-abortion laws have outlived their purpose if regarded in historical perspective. In 1942, this Court protected the civil right of a male person, even one duly convicted of crime, to control his own reproductive system. Is it any the less important that this Court protect the right of a female person to control her body and her reproductive system? We respectfully request this Court to recognize that the anti-abortion laws which force an unwillingly pregnant woman to continue pregnancy to term are a form of involuntary servitude without due conviction for a crime and without the justification of serving any national or public need. Louisiana (1968), the Court said: "We start from the premise that illegitimate children are not `nonpersons. As the highest court of New Jersey summarized the state of scientific knowledge, "Medical authorities have long recognized that a child is in existence from the moment of conception. The character of the child in the womb as a person is clearly recognized in the law of torts. It is significant that a majority of courts, keeping pace with advancing scientific knowledge, now hold that even a stillborn child may maintain a wrongful death action where his death was caused by a prenatal injury. The law of property has long recognized the rights of the child in the womb for purposes which affect the property rights of that child. For purposes of equity, too, the law has recognized the existence of the child in the womb. As a living human being he is therefore a person within the meaning of the Equal Protection Clause. Even if one somehow does not concede that the child in the womb is a living human being, one ought at least to give him the benefit of the doubt. Our law does not permit the execution, or imprisonment under sentence, of a criminal unless his guilt of the crime charged is proven beyond a reasonable doubt. The innocent child in the womb is entitled to have us resolve in his favor any doubts we may feel as to his living humanity and his personhood. The abortion is to his "irreparable injury" and by it he "is forever deprived of a basic liberty. It is appropriate to apply here the principles which govern the application of the Equal Protection Clause to another basic right-the right to be free from racial discrimination. There is no sufficient necessity which justifies a law which permits the killing of the child in the womb where it is not necessary to save the life of his mother. We are not concerned in this appeal with the question of whether a state law can constitutionally allow abortion where it is necessary to save the life of the mother. Rather the issue is whether the constitution permits the child in the womb to be killed where it is not necessary to save the life of his mother. To permit the child in the womb to be killed in such a case improperly discriminates against him on account of his age and situation. For the law does not allow a born child or an adult to be killed at the discretion of another or in any other situation where his killing is not necessary to save the life of another. Discrimination in employment on account of age is now forbidden by federal law which enunciates a strong public policy. The child in the womb should have the same right as his older brother or sister not to be killed where it is unnecessary to save the life of his mother. The brief was signed by 222 individual doctors, including medical school professors and those in private practice. Another brief filed in support of the Texas law, by the Texas Diocesan Attorneys, contained a similar description. Interest of the Amici [A]mici are physicians, professors and certain Fellows of the American College of Obstetrics and Gynecology who seek to place before this Court the scientific evidence of the humanity of the unborn so that the Court may know and understand that the unborn are developing human persons who need the protection of law just as do adults. In reviewing the Briefs filed in both cases it appears that no attempt was made to advise the Court of the scientific facts of life from conception to birth, or of the medical complications of induced abortion. An expansion of the right to privacy to include the right of a woman to have an abortion without considering the interests of the unborn person decides this question against the unborn. Assuming such a conflict, it is the position of the amici that the more fundamental and established of the conflicting rights must prevail where they clash. The right to life is most certainly the most fundamental and established of the rights involved in the cases facing the Court today. The medical hazards of legally induced abortion are all too often compared to the safety of a tonsillectomy or the "proverbial tooth extraction. The medical hazards of legal abortion should be presented to the Court in their total perspective through an analysis of this literature. It is imperative to note that when one focuses only on the legal abortion mortality rates from selected countries around the world, one can only see the risks of legal abortion through tunnel vision. The total medical picture cannot be understood without a look at the early and late physical and psychological complications. Indeed, these are the complications which affect the greater number of people and result in what a World Health Organization scientific group said was "a great amount of human suffering. It is deplorable to think that discussions of mortality can so easily exclude the child. Let us not forget that abortion kills children of varying ages and stages in development. The unheard voices of these little ones are our concern, and we deplore this violent trend which is turning the healing art of medicine into a source of efficient swift and sure destruction of human life. We deplore the condition of a society which calls physicians to exercise their art as a tool of death for those yet unborn. Most abortion proponents not involved in public efforts to promote their cause, admit that elective removal of the fetus is without psychiatric or medical justification. The fetus has not been shown to be a direct cause of any emotional disorder, and present medical capabilities make pregnancies safe. Almost always, other means than abortion are available to handle any medical or psychiatric complications of pregnancy. Indeed, if a woman wants her child, there are no medical or psychiatric indications that ever make an abortion necessary.
Comparison of the head elevation versus rotation methods in eliciting vestibular evoked myogenic potentials running with arthritis in the knee buy medrol 16 mg amex. Autonomic dysfunction has important implications for health and disease yet is clinically under recognized arthritis in neck and back of head medrol 4mg free shipping. Clinical signs of autonomic dysfunction are easily overlooked inflammatory arthritis diet remedies buy discount medrol 16 mg on-line, and neural activity in the autonomic nervous system is difficult to record directly the ultimate arthritis diet order medrol 4mg on line. Although sympathetic nerve function in peripheral nerves can be recorded with fine-tipped tungsten electrodes i have arthritis in my back what do i do order medrol 16mg with mastercard, this technique is difficult to apply clinically arthritis pain feels like medrol 16 mg fast delivery. Therefore, the assessment of autonomic function depends primarily on measuring the response of the autonomic nervous system to external stimuli. The measurements of sweating (Chapters 36 and 38), cardiovascular activity and peripheral blood flow (Chapters 37 and 39), and central autonomic-mediated reflexes provide insight into the broad range of disorders that affect the central and peripheral components of the autonomic nervous system-from the hypothalamus to the autonomic axons in the trunk and limbs. With better understanding of the clinical importance of measuring autonomic function and with increasing use of newly available tests of cardiovagal function, segmental sympathetic reflexes, postural hemodynamics, and power spectral analysis, the tests and measurements of autonomic function will be of greater benefit in patient care. Pain is mediated mainly through small nerve fibers, particularly in the autonomic nervous system. Measurements of their function can help elucidate the mechanisms underlying pain, especially peripheral pain. The emerging modalities for assessment of pain pathways include quantitative sensory tests, autonomic tests, microneurography, and laserevoked potentials (Chapter 40). Direct recording of spontaneous electric activity in nerves by microneurography is tedious but can be particularly helpful. Its integrative functions coordinate input from peripheral and visceral afferent nerves to orchestrate a dynamic balance among organ systems. Its adaptive functions react moment by moment to the various forms of stress the body experiences. It consists of sympathetic (thoracolumbar) and parasympathetic (craniosacral) divisions. The enteric nervous system, located in the wall of the gut, is considered a third division of the autonomic nervous system. The autonomic nervous system thus regulates and coordinates such physiological functions as blood pressure and heart rate, respiration, body temperature, sweating, lacrimation, nasal secretion, pupillary size, gastrointestinal motility, urinary bladder contraction, sexual physiology, and blood flow to the skin and many organs. Autonomic neuropathies that disconnect central autonomic centers and autonomic ganglia from their peripheral effectors 617 618 Clinical Neurophysiology may result in deficits in autonomic function. Examples include orthostatic hypotension due to adrenergic failure, heat intolerance due to sudomotor failure, gastroparesis, hypotonic bladder, and erectile failure. Autonomic centers disconnected from inhibitory influences may give rise to episodic autonomic hyperfunction. Examples include autonomic dysreflexia and hypertonic bladder following spinal cord trauma, diencephalic syndrome following head injury, hypertensive surges of baroreflex failure following irradiation to the carotid sinuses, auriculotemporal syndrome, and catecholamine storms in pheochromocytoma. Autonomic disturbances frequently accompany neurologic illnesses affecting motor or sensory systems or may occur in isolation. More frequently, accurate characterization, localization, and grading of autonomic dysfunction require a careful history to elicit subtle symptoms, a neurological examination attentive to autonomic signs, and testing in a clinical autonomic laboratory. The differential diagnosis of autonomic failure includes the peripheral neuropathies (many of which involve autonomic fibers), central degenerative disorders, and medical disorders that impact the autonomic nervous system. Peripheral autonomic failure frequently occurs in small fiber neuropathies, particularly in diabetes mellitus and amyloidosis. Autonomic disturbances are common also in botulism, diphtheritic neuropathy, and Chagas disease. The presence of autonomic failure has important implications for clinical management as well as for prognosis. Disruption of autonomic function can influence the longterm risks of morbidity,1, 2 mortality,35 and intraoperative mortality. Unlike the easily reproducible function of somatic motor or sensory nerves, autonomic nerve function is difficult to evaluate precisely in humans. In general, evaluation of autonomic function has been restricted to noninvasive recordings of heart rate, blood pressure, blood flow, or sweat production. The interpretation of the results of these tests may be difficult, because (1) the effector organs react slowly to variations in neural input, (2) the interactions of sympathetic and parasympathetic outputs at a single target level are complex, and (3) autonomic responses are affected by pharmacologic, hormonal, local chemical, and mechanical influences. This chapter provides an overview of some aspects of autonomic function that may help with interpreting the results of noninvasive autonomic tests commonly used clinically. Purpose and Role of Autonomic Testing · Recognize the presence, distribution, and severity of autonomic dysfunction. Quantitatively evaluate autonomic dysfunction over time To define the progression or remission of autonomic disease To assess the response to therapy. Visceral Afferents Visceral receptors generally are slowly adapting mechanoreceptors or chemoreceptors that have a low level of spontaneous activity and are innervated by small myelinated and unmyelinated fibers. Organization of the sympathetic and parasympathetic outputs of the autonomic nervous system. This reflects important differences in the functional organization of autonomic and somatic efferents. Autonomic output involves a two-neuron pathway that has at least one synapse in an autonomic ganglion. At most sympathetic neuroeffector junctions the primary postganglionic neurotransmitter is norepinephrine, which acts on the various subtypes of - and -adrenergic receptors. The primary postganglionic neurotransmitter at all parasympathetic neuroeffector junctions is acetylcholine, which acts on the various subtypes of muscarinic receptors. Whereas the main consequences of denervation in the striated muscle are paralysis and atrophy, postganglionic efferent denervation produces an exaggerated response of the target when it is exposed to the neurotransmitter. This phenomenon, called denervation supersensitivity, is evidence of a lesion involving postganglionic neurons in which the remaining neuroeffector receptors are upregulated. Activity of most autonomic effectors is modulated by dual, continuous sympathetic, and parasympathetic influences. It predominates in control of the salivary glands, sinoatrial node, gastrointestinal tract, and bladder. The sympathetic and parasympathetic systems may interact at several levels, including that of the central nervous system, autonomic ganglia, neuroeffector junction, and target organ. Postganglionic autonomic neurons send unmyelinated (type C) axons to innervate peripheral organs. At most sympathetic neuroeffector junctions the primary postganglionic neurotransmitter is norepinephrine. In the sweat glands, sympathetic effects are mediated principally by acetylcholine. The primary postganglionic neurotransmitter at all parasympathetic neuroeffector junctions is acetylcholine. Sympathetic functional units include skin vasomotor, muscle vasomotor, visceromotor, pilomotor, and sudomotor units. Their postganglionic fibers destined for the trunk and limbs follow the course of spinal nerves or blood vessels or both. Spinal fibers join the peripheral spinal (somatic) nerve through the gray ramus communicans. These fibers provide vasomotor, sudomotor, and pilomotor input to the extremities and trunk. Sympathetic fibers are intermingled with somatic motor and sensory fibers, and their distribution is similar to that of the corresponding somatic nerve. Most sympathetic fibers are destined for the hand and foot and are carried mainly by the median, peroneal, and tibial nerves and, to a lesser extent, the ulnar nerve. For example, nociceptive stimuli reflexively activate segmental circuitry that generates excitation of vasoconstrictor outflow to skeletal muscle and inhibition of vasoconstrictor outflow to the skin. For example, during execution of the cold pressor test, decreases in cutaneous blood flow in an arm exposed to ice cold water are accompanied by cutaneous vasoconstriction in the contralateral forearm. All segmental spinal reflexes are subject to supraspinal modulation through several parallel pathways arising in the hypothalamus, pons, and medulla and innervating the sympathetic preganglionic neurons. Indirect methods include noninvasive tests of sudomotor and cardiovascular function described in Chapters 3639; measurement of plasma norepinephrine concentration in forearm veins with the subject supine and standing;18, 19 assessment of splanchnic20, 21 and cerebral blood flow22, 23 using Doppler techniques; and assessment of sympathetic innervation of the heart using radioisotope methods. This technique allows multiunit recordings of two different types of outflow: skin sympathetic nerve activity and muscle sympathetic nerve activity. Postganglionic sympathetic fibers travel with spinal motor and sensory fibers or with arteries to provide vasomotor, sudomotor, and pilomotor innervation to the trunk and limbs. Most sympathetic fibers supplying the foot are carried by the peroneal and tibial nerves. Unlike somatic motor neurons, sympathetic preganglionic neurons are not monosynaptically driven by afferent input. Sympathetic reflexes are segmentally biased, predominantly uncrossed, and exhibit ipsilateral, function-specific, reciprocal and nonreciprocal patterns of response. Sympathetic function can be assessed noninvasively by indirect techniques, or invasively by direct microneurographic recording of postganglionic sympathetic nerve activity. Decreased or increased environmental temperature can produce selective activation of the vasoconstrictor or sudomotor system, respectively, with suppression of activity in the other system. Emotional stimuli or inspiratory gasp also increases spontaneous skin sympathetic activity, but in this case the bursts are caused by simultaneous activation of sudomotor and vasomotor impulses. Arteriovenous skin blood flow is carried by low-resistance arteriovenous shunts, which receive abundant sympathetic vasoconstrictor input and have a key role in thermoregulation. Skin blood flow is also controlled by somatosympathetic reflexes13, 14 and three local axon reflexes: (1) the axon flare response, (2) the sudomotor axon reflex, and (3) the venoarteriolar reflex. The venoarteriolar reflex is mediated by sympathetic vasomotor axons innervating small veins and arterioles. Skin vasomotor activity has been studied clinically by using several noninvasive methods for measuring skin blood flow, including plethysmography and laser Doppler flowmetry. The segmental pattern of distribution of sudomotor fibers to the trunk and limbs is irregular and varies substantially among individuals and even between the right and the left sides of an individual. Key Points · Sympathetic vasomotor, pilomotor, and sudomotor innervation of skin effectors has primarily a thermoregulatory function. However, this activity in the arm and leg can be dissociated during mental stress and during forearm ischemia after isometric exercise. The respiratory cycle, changes of posture, or the Valsalva maneuver may modulate the muscle sympathetic activity caused by changes in arterial pressure. However, hypercapnia, hypoxia, isometric handgrip, emotional stress, or the cold pressor test increase muscle sympathetic activity despite unchanged or increased arterial pressure. Parasympathetic control is provided by cardiovagal neurons in the nucleus ambiguus and dorsal motor nucleus in the medulla. Effects mediated by the vagus nerve have a shorter latency and duration than those mediated by the sympathetic nerves. Heart rate has spontaneous fluctuations, which reflect changing levels of autonomic activity modulating sinus-node discharge. Heart rate variability is correlated inversely with age in normal subjects at rest. Upright posture in humans dramatically increases sympathetic nerve activity and produces a large increase in low-frequency heart rate power. The primary role of arterial baroreflexes is the rapid adjustment of arterial pressure around the existing mean arterial pressure. Baroreflexes induce short-term changes in heart rate opposite in direction to the changes in arterial pressure, thus increasing heart rate variability. The carotid baroreflex has been studied by applying negative and positive pressures to the neck, which increase and decrease, respectively, carotid sinus transmural pressure. Autonomic Physiology 625 rate responses to changes in arterial pressure induced by intravenous infusion of vasoconstrictor or vasodilator agents. At higher intensity, responses depend on both the motor command and the muscle chemoreflexes. Atrial receptors innervated by vagal myelinated fibers are activated by atrial distention or contraction and initiate reflex tachycardia caused by selective increase of sympathetic outflow to the sinus node. Cardiopulmonary receptors with unmyelinated vagal afferents, similar to arterial baroreceptors, tonically inhibit vasomotor activity. Unlike atrial baroreceptors, cardiopulmonary receptors provide sustained rather than phasic control in sympathetic activity and vasomotor tone in the muscle and have no major effect in controlling heart rate. Venous pooling activates receptors in small veins of the skin, muscle, and adipose tissue; the result is vasoconstriction in the arterioles supplying these tissues. During limb dependency, this local reflex vasoconstriction may decrease blood flow by 50%. The main 626 Clinical Neurophysiology vasoconstriction in the arterioles supplying skin, muscle, and adipose tissue. In addition, central blood volume decreases following transcapillary filtration of fluid into the interstitial space in the dependent tissues. The decrease in mean arterial pressure is prevented by a compensatory vasoconstriction of the resistance and capacitance vessels of the splanchnic, renal, and muscle vascular beds. The initial adjustments to orthostatic stress are mediated by baroreflexes and cardiopulmonary reflexes. During prolonged orthostatic stress, additional adjustments are mediated by humoral mechanisms, including the argininevasopressin and reninangiotensinaldosterone systems. When venous filling in the dependent parts increases intravenous pressure to 25 mm Hg, it activates a local axon reflex, called the venoarteriolar reflex, which further contributes to adaptation to orthostatic stress. Patients with autonomic failure have disturbed neural reflex arterial vasoconstriction, and this is the primary mechanism of orthostatic hypotension. The inability to increase vascular resistance allows considerable venous pooling to occur in the skeletal muscle, cutaneous, and splanchnic vascular beds of the dependent parts. The abdominal compartment (splanchnic circulation) and perhaps skin vasculature are the most likely sites of venous pooling. The counterregulatory mechanism that reduces pooling in the lower extremities is activation of the skeletal muscle pump. Active muscle contraction increases intramuscular pressure, which opposes the hydrostatic forces and reduces venous pooling in the legs.
An important educational goal relevant to the growth of evolutionary medicine is to incorporate instruction in evolutionary biology into premedical and medical school education knee brace for arthritis in the knee medrol 4mg on line. Currently arthritis medication in canada purchase 4 mg medrol overnight delivery, few medical schools have evolutionary biologists on their faculties arthritis pills for dogs buy 16mg medrol with mastercard, and none teach evolutionary biology as a basic medical science arthritis in neck and tmj 4mg medrol amex. Physicians and medical researchers may learn something about evolution before medical school arthritis group patient portal generic 4 mg medrol overnight delivery, but few have anywhere near the level of knowledge demanded for other basic sciences hip joint arthritis pain location purchase 4mg medrol otc. An evolutionary view would correct mistaken notions of the body as a designed machine and would provide physicians with a better sense for the organism and what constitutes disease. Specific renovations of the medical curriculum would also infuse evolutionary thinking into medicine. But it is likely that new national policies would be needed to educate physicians, allowing them to make full use of evolution as a crucial basic science for medicine. Evolutionary medicine is a young field, and as more discoveries demonstrate how evolution-based thinking can improve the understanding and treatment of medical disorders, it should become clear that fundamental knowledge of evolution belongs in the medical toolkit. Defining virulence the phase model of virulence the trade-off model Vertically transmitted parasites How well do optimality models predict virulence? The average number of Diseases caused by parasite or pathogen infections impair normal functioning in organisms. Studies of the evolution of the virulence of infectious diseases strive to understand the expression of these symptoms as the result of the evolutionary process. This approach is primarily focused on the evolution of parasites (here used to include pathogens), but it may also consider the coevolution of hosts and parasites. Until about 30 years ago, it was widely accepted that the harmful symptoms of infectious diseases were the side effects of poorly adapted parasites, and that over time virulence would therefore generally evolve toward avirulence. The underlying logic was that a well-adapted parasite should not harm its host, as doing so would deplete its own resource. This view was challenged in the 1980s by Roy Anderson, Robert May, and Paul Ewald, who argued that virulence is often a necessary consequence when parasites exploit their hosts, and depending on the specific conditions, the optimal level of virulence. Virulence is now understood as a trait whose evolution can be analyzed within the general framework of evolutionary biology, thus considering the roles of history, chance, and natural selection. The evolution of virulence is not only of academic interest; its conceptual framework also has implications in various applied fields, such as human and veterinary medicine and agriculture. In particular, public health workers secondary infections resulting from a primary infection in a population of susceptible hosts. The passing of a parasite between two hosts that are not related in direct line, for example, vector-borne transmission and sexual transmission. Fitness is said to be inclusive because it considers the fitness of related individuals. This virus causes myxomatosis and has been used to control rabbit pests in Australia and Europe. An infective agent transmitted among hosts and growing or replicating within hosts. Parasites with maternal (vertical) transmission that manipulate host reproduction to increase their representation in the offspring of the next host generation, for example, by killing or feminizing male offspring. More precise definitions, such as parasiteinduced host death rate or host fecundity reduction, are used for specific situations. This definition includes any fitness effect the parasite has on the host, 742 Evolution and Modern Society the first contact of a parasite with a host that it usually does not infect, often called accidental infection. In phase 3 the parasite has evolved for some time in a particular host and has adapted to the specific conditions of this host population. The phase model emphasizes that not all aspects of parasite virulence can be understood as a result of adaptive evolution. The highly virulent Ebola virus does not circulate long enough in humans to evolve an optimal level of virulence. It is clearly able to persist in humans, but it may not have had time to reach an optimal level of virulence. Much older human diseases, such as tuberculosis and leprosy, are likely to be in phase 3. Phase 1: Accidental Infections whether that effect is an incidental by-product of the infection or an adaptive trait for the parasite. This definition does not, however, explain how virulence evolves, because it does not specify the link between parasite fitness and virulence. Most attempts to understand the evolution of virulence are based on models of parasite evolution and therefore consider only aspects of virulence that are important for parasite fitness. For an exclusively horizontally transmitted parasite, host mortality is important, as the parasite might die with the host, whereas reduced host fertility or sexual attractiveness-which are important for host fitness-may be of little concern for the parasite. For example, congenital rubella syndrome is a serious illness of babies born to mothers who became infected with the rubella virus during the first trimester of pregnancy. It is a big concern for the human host but is unlikely to have an impact on the evolution of the rubella virus. Thus, understanding the evolution of virulence requires detailed knowledge about the host-parasite system in question. In the application of models of optimal virulence to actual diseases, the key factors to consider are the mode of parasite transmission and the trade-offs among parasite fitness components. Virulence may be further categorized by distinguishing between effects directly beneficial for the parasite. Examples of effects with a direct benefit for the parasite include parasitic castration (which liberates resources for parasite reproduction), impaired host mobility (which may increase access to the host by vectors that transmit the parasite further), and parasiteinduced changes in host behavior (which may increase chances of transmission). A refined version of this twostage scenario tries to combine the different aspects of virulence evolution and expression into a unified framework (Ebert and Bull 2008). For some of these diseases, untreated infections can approach 100 percent mortality rates. Transmission chains are short, and epidemics do not persist, so the parasites have little opportunity to adapt to their new hosts. At first glance, this case might seem to support the view that novel diseases are highly virulent. However, the most virulent accidental infections are most likely to be recognized, whereas avirulent accidental infections will often go unnoticed, thus producing a strong sampling bias. In fact, avirulent accidental infections may outnumber virulent infections, as experimental transspecies infection trials suggest. Thus, highly virulent novel diseases are the exception, not the rule, although they may have profound impact on humans and natural populations. Accidental infections have played and continue to play an important role in applied fields such as medicine and agriculture. In agriculture, highly virulent novel infections have been used in pest control, as, for example, to control the very dense populations of European rabbits in Australia and the Evolution of Parasite Virulence United Kingdom with the Myxoma virus, which is derived from a virus of a related host species. Phase 2: Evolution of Virulence Following Successful Invasion 743 After a parasite infects a novel host species, its transmission success will determine whether it will persist and spread in this species. Initial spread is typically epidemic, and the level of virulence of the nonadapted parasite is unlikely to be close to optimum. Every endemic infectious disease has made the successful transition from phase 1 to 2 at some stage in its evolutionary history, but the number of observed cases is very low, despite many more examples of accidental infections (more than 1000 human diseases, so-called zoonoses). Phase 2 can also help us understand the emergence and spread of novel variants (mutants) of a parasite in an established host-parasite association. These mutants may have extreme effects and may spread rapidly, causing an epidemic and being unaffected by existing host defenses. If they occur frequently, a parasite population may never reach an optimum virulence and thus will remain in phase 2 (Bull and Ebert 2008). In this case, the fitness consequences of having suboptimal virulence are likely to be minor relative to the fitness gains the mutants achieve by evading host immunity and other defenses. Studying parasites in phase 2 illuminates how the tempo and mode of virulence evolution proceeds in real time. A highly virulent strain of this virus was introduced to Australia to control European rabbits, an invasive species that was causing extensive damage. Within a few years the average virulence of the parasite had changed drastically, attaining a new level far below the virulence of the original strain (Fenner and Kerr 1994). Apparently, the original virulence had been far above the presumed optimum, although not so high that it had prevented the spread of the virus. The Myxoma example leaves many questions open, as multiple factors changed simultaneously. But it does demonstrate that virulence can evolve rapidly, that virulence evolution does not necessarily lead to complete avirulence, and that virulence coevolves with the host (Fenner and Kerr 1994). Laboratory experiments that follow parasite evolution after a change of environmental conditions or a host shift are in effect creating phase 2 situations. This situation is particularly true for serial passage experiments, which played an important role in vaccine development, and also for the understanding of virulence evolution. In these experiments parasites are passaged in novel hosts with transmission controlled by the researcher (in some cases, the parasite might go extinct without this intervention). Evolution typically results in a strong increase in virulence in the host in which the passages take place. This attenuation of virulence makes these parasites good candidates for vaccines, as the immune response of the former host still recognizes the parasite, but its low virulence prevents disease or limits its severity. This increase is likely driven by within-host competition among parasite variants, with the most prolific variants having the highest chance to be transmitted during the next passage. Phase 3: the Evolution of Optimal Virulence Parasites that persist for some time in a host are expected to evolve an optimal level of virulence, that is, the level of virulence at which parasite fitness is maximal. It is widely thought that this optimum is characterized by trade-offs among different parasite fitness components. Thus, a key difference between phase 2 and phase 3 is that in phase 2, the parasite is not yet subject to the constraint imposed by the trade-offs. The Myxoma virus example was the first to show the existence of a trade-off, in this case between the rate at which rabbits clear the infection (host-induced parasite death) and the rate at which the parasite kills the host (and itself). A mathematical model, latter called the tradeoff model, and the observed data agreed well. In the mathematical model first applied to analyze the Myxoma data, virulence is defined as the parasite-induced host death rate. Other detrimental effects the parasite may have on the host, such as reduced mating success and fecundity, are not considered because they are not fitness components of the parasite. This simplification is acceptable under the assumption that parasite-induced host death rate is positively correlated with the various expressions of morbidity. These positive correlations also justify the use of surrogate measures of virulence in empirical studies, 744 Evolution and Modern Society ignores changes over time in the density of susceptible hosts, including those changes that may occur as the parasite itself evolves. Multiple Infections, Inclusive Fitness, and Virulence such as host fatigue, sensitivity to stress, fever, or other physiological parameters. However, it is important to keep in mind that correlations between parasite-induced host death rate and other disease-related traits may be weak or may have a negative sign. For example, many parasites of invertebrates castrate their hosts, which eliminates host fecundity but allows the parasite to keep its host alive for much longer than a noncastrator would be able to . In the following discussion of optimal virulence, parasite-induced host mortality is used as a definition for virulence. The first and still most used model for the evolution of virulence is the trade-off model (Anderson and May 1982). This model is a powerful starting point for analyzing the evolution of virulence, although its simplicity implies certain assumptions and makes it vulnerable to various criticisms. The model stresses the importance of trade-offs between parasite-induced host death and other parasite fitness components. In its simplest form, parasite fitness is estimated as the number of secondary infections that result from a primary infection, R0: R0 ј bN; aюrюm where b is the transmission rate in a susceptible host population of density N, a is virulence (parasite-induced host death rate), r is the rate at which hosts clear infections, and m is the host background (parasite-independent) mortality rate. Without trade-offs, parasite evolution would maximize b and minimize the total parasite death rate (a + r + m), thus driving virulence to zero. A positive correlation between b and a, or a negative one between a and r (as in the case of the Myxoma example), constrains the evolution of virulence. This simple trade-off model relies entirely on the assumption that between-host transmission is the quantity maximized by parasite evolution. Although 30 years old, the hypothesis that between-host transmission is crucial for the evolution of virulence is still not strongly supported by empirical evidence. A critical test will be to show that transmission success has the assumed hump-shaped relationship with virulence. Empirical studies that tested this prediction were conducted with unicellular parasites that infect mice, butterflies, and water fleas (Daphnia). Some of the major limitations of the simple trade-off model are that it ignores the role of multiple infections and within-host evolution of the parasites, kin structure of parasites, and host genetic variation. The model also In the 1990s the trade-off model was extended to include within-host competition. Within-host competition describes scenarios in which different variants of parasites compete within hosts, which strongly influences both their likelihood of transmission to the next host and the level of virulence expressed in the multiply infected hosts. Parasite variants that replicate more quickly are assumed to be superior in within-host competition, even if this reduces host survival and thus shortens the period for transmission to take place. Because higher replication rate is associated with higher virulence, average virulence is expected to be higher in populations with frequent multiple infections than in those with single infections, all else being equal. As a consequence, more virulent parasite variants may dominate although they do not maximize the R0 as predicted by the simple tradeoff model. However, more complex models incorporating additional factors that might occur with multiple infections have been developed that predict the opposite result under specific circumstances. In particular, cooperation among parasites to exploit the host or parasite strategies to exploit one another may lead to the evolution of lower virulence. Empirical tests on the role of multiple infections have generally supported the key assumption and prediction of the basic multiple infection model. Thus, higher within-host multiplication rates have been found to be associated with both superior competitive ability and higher virulence.
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