Joel A. Kaplan, MD, CPE, fa cc

• Professor of Anesthesiology
• University of California, San Diego
• San Diego, California
• Dean Emeritus, School of Medicine
• Former Chancellor, Health Sciences Center
• University of Louisville
• Louisville, Kentucky

In such hyphae treatment effect definition order 20 mg pepcid with mastercard, the two nuclei forming the 82 Mushrooms: Cultivation medicine 6 clinic buy cheap pepcid 40 mg line, Nutritional Value medicine lake buy 20 mg pepcid visa, Medicinal Effect medicine joji generic 40 mg pepcid free shipping, and Environmental Impact heterokaryon divide simultaneously treatment bladder infection purchase 40mg pepcid mastercard, sending two non-sister nuclei into the terminal cell treatment 5 of chemo was tuff but made it order 40mg pepcid fast delivery, one nucleus into the penultimate cell treatment arthritis generic pepcid 40mg on-line, while the fourth nucleus remains in the unfused hook cell medications similar to vyvanse buy cheap pepcid 20 mg on line. In the common A (A = B) heterokaryon the aerial mycelium is sparse, giving rise to the common name "flat" for this heterokaryon; the cells vary in the number of nuclei they contain per cell, there are no clamp connections, and partially formed septa are frequently encountered. The compatible reaction, which may lead to the formation of a fruiting body, occurs when mycelia heteroallelic for both mating type factors are confronted. With equal numbers of spores of each mating type (AxBx, AxBy, AyBx, and AyBy) possible, confrontations of mycelia arising from these spores will give rise to equal frequency of the following reactions: compatible (A B), hemicompatible (A = B), hemicompatible (A B =), and incompatible (A = B =). Among the cultivated edible fungi there are several examples of tetrapolar heterothallism, including Lentinula edodes, Pleurotus ostreatus, P. Although there are complexities in the genetic manipulation of the tetrapolar system, this is offset by a wealth of basic information derived from studies of Schizophyllum, Coprinus, Flammulina, and others which makes those species that have bifactorial incompatibility attractive to growers and breeders. Hormonal (Pheromonal) Control the term hormone has been used in the fungi in its classical sense as an organic compound produced in one part of the organism and transferred to another part where it elicits a special response. Currently, this term is used interchangeably with pheromone, which is defined as a chemical substance that acts at a distance. The best-documented cases of hormonal regulation of sexuality in the fungi are those involving some of the aquatic fungi. Raper revealed the sequential development of sex organs of Achlya (class Oomycetes) under the control of several hormones, and two of these (antheridiol and oogoniol) have now been chemically identified. In Allomyces (class Chytridiomycetes) the female gametes have been shown to produce a hormone, sirenin, which attracts the male gametes to them. In the class Zygomycetes several heterothallic fungi have been shown to produce hormones that are responsible for the growth in air of zygophores (stalks that will bear zygospores) toward one another. In heterothallic species the + and - strains produce different hormone precursors. When these hormone precursors (prohormones) diffuse into the air and reach the strain of opposite mating type, they are converted to active hormones, and it is these active hormones that cause the zygophores to grow toward one another. The system of control is complex and much remains to be discovered about the induction of the morphogenetic changes. In the higher fungi, the best-documented study of hormonal control in sexuality is in the ascomycete Ascobolus. The sexual organs (antheridia and ascogonia) are produced only when the A and a mycelia are in close proximity to one another. Oidia, normally asexual reproductive units, may become activated in the presence of mycelium of opposite mating type, and an activated oidium may induce the growth of trichogynes toward the oidium when these two bodies are within a distance of 100 mm from one another. If the position of the oidium is changed, there will be a new growth from the trichogyne at the point nearest to the oidium with growth occurring in the direction of the oidium. Activated oidia placed on mycelium of the same mating type on which ascogonia with trichogynes were present will behave as though of compatible mating type, in that conjugation will occur between the trichogyne and the oidium (or antheridium); but the ascocarp ceases growth after a short initial period of development. Bistis5 has also demonstrated a role for sexual hormones in the ascomycete Neurospora crassa. Several decades ago a role for hormones in sexuality of this species had been suggested, but a definitive experimental demonstration for hormones in sexuality was not presented until the report of Bistis. There are cases in which observations of directed growth of hyphae might be interpreted as being the result of hormonal activities. For example, in their study of hyphal fusions of Schizophyllum commune in which hyphae from confronting mycelia were studied microscopically, Ahmad and Miles1 reported instances in which these hyphae curved and grew toward one another. In these studies it was also reported that there was a significantly higher frequency of hyphal fusions in confrontations involving heteroallelic A (i. A mycelium is necessary for spores to produce the attractant, and the spores must be viable. In a number of studies of fruiting body development of Basidiomycetes, a role for hormones has been demonstrated although the chemical nature of the hormone may not be known. While a number of plant hormones (auxins, gibberellins, ethylene) have been found in Basidiomycetes, a hormonal role for these in the fungi has not been demonstrated. Some experimentation has indicated a role for a compound produced in the gills and causing stipe elongation, but as yet no chemical identification has been obtained. It is anticipated that soon we will have more information on hormones and their roles in the fungi because there are now more techniques available for identifying compounds active in low concentration. Nonsexual reproduction is commonly referred to as asexual reproduction (reproduction without sex), and these terms are used interchangeably in this book. Other terms denoting reproduction in the absence of sexuality are somatic or vegetative reproduction. As previously noted, nonsexual reproduction does not involve the union of nuclei, or sex cells, or sex organs. That is, nonsexual (asexual, somatic, vegetative) reproduction occurs when progeny are formed from a single parent. There is no contribution from a second parent, and the offspring are genetically identical to the parent from which they arose. This is in marked contrast to sexual reproduction, where variation among the offspring is the rule. The advantage of nonsexual reproduction to the fungus is that large numbers of progeny can be formed from an individual that is well adapted to a particular habitat, set of environmental conditions, nutritional availability, or even need, in the case of utilization by humans. Those offspring that reach a favorable substrate will grow and in turn reproduce under appropriate 84 Mushrooms: Cultivation, Nutritional Value, Medicinal Effect, and Environmental Impact environmental conditions. Many of the asexual reproductive units are easily disseminated and germinate rapidly so that the fungus can spread over a wide area within a short time. The obvious disadvantage of reproduction solely by nonsexual means is that the environmental conditions may change and not be satisfactory for the germination of the disseminated asexual reproductive unit, or for its subsequent growth and ability to become established in the new habitat. As long as the environmental conditions remain unchanged, there is a certain advantage to the species inherent in the genetic stability of asexuality. It is when the environmental conditions change in an unfavorable way that nonsexual reproduction is a disadvantage, because then only the infrequent mutations that permit growth under the changed conditions will allow the organism to survive. There are four general methods, some of which are found more frequently than others: 1. This is commonly found in yeasts with each bud formed giving rise to a new individual. The buds in some species arise from different places on the parent cell, but in other species they develop from the same place (one of the poles of the ellipsoidally shaped cell). This is by far the most common and best-known method of asexual reproduction in fungi, and thus we treat it in more detail. B) some specialized asexual reproductive structures, the various types of nonsexual reproductive units will now be examined more fully. At the level of subdivision distinctions are made on the basis of presence or absence of sexual spores and, when present, the type of sexual spore. At lower levels the asexual spore and the structures in which they are located are of taxonomic use. Spores vary in color, in size, in shape, and in the number of cells comprising them. There is also variation in the arrangement of the cells supporting the spores and in the manner in which they are borne. Combinations of these various characteristics result in tremendous variation of spore types and structure, and some fungal species may produce more than one type of asexual spore. Sporangiospores (Motile and Nonmotile) Nonsexual spores may be borne within a structure. To distinguish these spores from other spores they are sometimes referred to as sporangiospores. Sporangia are saclike structures that in some species contain spores that are motile, and in other species nonmotile spores are contained within the sporangium. The motile spores are referred to as zoospores; the nonmotile spores are called aplanospores. The whiplash flagellum is divided into two parts, with a basal portion that is much longer than the terminal portion, which is usually very short and flexible. The tinsel flagellum is quite distinct in that it has a number of lateral hairlike projections, called mastigonemes, along its entire length. For example, in the Chytridiomycetes, of which Allomyces is a member, the zoospores have a single, posteriorly inserted, whiplash flagellum; in the Oomycetes, of which Achlya is a member, the zoospores have Overview of the Biology of Fungi 85 two flagella which are laterally inserted, but the tinsel is anteriorly directed, and the whiplash posteriorly directed. Many details of flagellar structure have been learned from studies using the electron microscope, and it is interesting to note that transverse sections through the flagellum reveal a core (the axoneme) of two centrally located microtubules surrounded by nine pairs of microtubules near the periphery, an arrangement that is found in the flagella of all eukaryotic organisms. Nonmotile sporangiospores are produced in sporangia that form at the tips of specialized stalklike hyphae known as sporangiophores. The terminal portion of the sporangiophore generally becomes swollen, forming a dome-shaped columella. Details of the developmental events at the electron microscopic level are known from only a few studies, but it appears that these vesicles arise from the endoplasmic reticulum, and that the membranes of the vesicles fuse and are converted into tubules that branch and extend throughout the cytoplasm. Segments of protoplasm containing nuclei are cleaved out in this way, and these will become the sporangiospores. A wall is deposited outside the plasma membrane of the sporangiospore, this membrane having been derived from the membranes of the vesicles. Developmental details regarding the initial nuclear condition, uninucleate or multinucleate, of the developing sporangiospores are uncertain. These lateral sporangia are smaller than the terminal sporangium and are termed sporangioles (sporangiola). Conidia In contrast to sporangiospores, which are produced within a structure, conidia are borne externally, either terminally or laterally on hyphae or specialized hyphae called conidiophores. Conidiophores may be unbranched or branched in a multitude of ways, and they bear conidiogenous cells, which ultimately produce the conidia. Thallic development of conidia occurs when the hypha undergoes fragmentation or septation and the complete cell with its wall is delimited and may then swell. In blastic development there is a swelling process of only a portion of the cell, which gives rise to the conidium. The phialides do not elongate, and the conidia are produced in succession from the narrow neck of the phialide, forming chains. Oidia behave like spores, but sometimes they also may function in sexuality, as has been demonstrated in the ascomycete Ascobolus and in the basidiomycete Coprinus. Chlamydospores Chlamydospores are thick-walled spores that are formed from vegetative cells and may be in chains or located in a terminal or intercalary position. Chlamydospores with their thick walls provide for survival under adverse environmental conditions. Sclerotia Survival under adverse environmental conditions is also provided by sclerotia (sing. The sclerotium is a hard, resistant body made up of fungal tissue, which after a period of dormancy germinates when conditions are favorable to give rise to a mycelium or other fungal structure. Sclerotia have been indicated as playing a vital role in the fruiting of the edible morel, Morchella. Mycelia Fragments In nature, nonsexual reproduction may be brought about when a mycelium becomes separated by any means into two or more parts. In the laboratory, mycelial fragmentation is one of the most commonly used means of propagation of fungi. The procedure is simply to take a sterile scalpel and cut out a small block of mycelium from a culture and transfer this aseptically to a nutritionally suitable sterile medium for incubation under appropriate conditions. It is not germane to the present treatment of spore germination to detail the many mechanisms of fungal spore germination, but we point out some general aspects of the topic. Factors Affecting Germination Whereas some spores will germinate immediately on being released from the parent structure if the environmental conditions are suitable, other species produce spores that remain dormant for a period of time. Endogenous dormancy is imposed from within and may be due to the presence of low moisture content within the spore or the presence of inhibitors of germination. Thus, a wall that is relatively impermeable to water and a low water content of the spore will combine to keep the spore in the dormant stage, and this is a constitutive feature of the spores of certain species of fungi. The inhibitors of germination may be volatile or nonvolatile substances, and these must be removed for germination to take place. In addition, there are compounds that stimulate germination, and one of the ways in which these stimulators act is by overcoming the effects of self-inhibitors. Among the edible mushrooms there are some species in which breeding is difficult because of poor or inconsistent germination of basidiospores. The outstanding case in which this is true is that of Agaricus bisporus, but it is also true with Volvariella volvacea; and in a number of other species, the scientist is plagued by inconsistent germination. Early observations indicated that isolated spores germinated very infrequently; but when many spores were close together, good germination occurred. A few spores germinated early and these seemed to stimulate the germination of other spores. These observations led to numerous experimental studies based on the premise that gaseous substances stimulated germination. This was supported by the finding that spore germination increased when the spores were in the same gaseous environment as the living mycelium of A. Numerous volatile organic acids were then tested for a possible effect on spore germination, and isovalerate, produced by the mycelium, has been implicated as the stimulator of germination in a number of studies. The mode of action that has been suggested is that germination of the spores is suppressed by the accumulation of carbon dioxide in the spores and that isovalerate is a direct precursor of a carbon dioxide acceptor b-methylcrotonyl coenzyme A. In some species of fungi, nutrients are required for germination, but in other species the spore contains sufficient nutrients for germination if water and suitable environmental conditions exist. The environmental factors important in spore germination are the same as those for mycelial growth and fruiting body formation: temperature, pH, aeration, and light. The optimal values for these three different developmental stages of fungi (spore, mycelium, and fruiting body) will differ, although commonly within the same range of values. The nutritional requirements for germination are difficult to generalize, because there are species, on the one hand, whose spores require nothing beyond water and an aerobic condition and, on the other hand, there are species that require inorganic salts and organic compounds such as glucose, or specific vitamins, or amino acids. Griffin18 points out that in several fungi, carbon dioxide has been shown to be a requirement for spore germination and growth and, more importantly, emphasizes that carbon dioxide may be a universal requirement. Measurement Plant pathologists have long been concerned with studies of spore germination because of their interest in prevention of the spread of fungal diseases by spores. Thus, many of the techniques that have been developed for testing the effectiveness of various treatments to prevent spore germination have been developed by workers in the field of plant pathology, and certain standard procedures have been established. Of greatest interest from the standpoint of edible mushrooms, however, is the germination of basidiospores. Although the basidiospore commonly takes in water and swells as a first stage in germination, it is the emergence of the germination tube that is commonly accepted as the criterion of germination. Thus, microscopic examinations are made at intervals of time to determine the percentage of spores that have formed germ tubes, and these structures are called germlings. Besides the effects of nutritional and environmental factors on germination, the age of the fruiting body in reference to the time of discharge of the spores may also influence results, as will the density of spores in the germination chamber. Only when we take the fungi into the laboratory and establish pure cultures are the fungi truly separated during their growth from other organisms. This living together, which is the normal situation in nature for all living things, is referred to as symbiosis. Symbiosis is commonly studied by taking a particular organism, or group of organisms, and examining any special relationships that species of a different taxon may have with it. For example, the relationship of insects with pollination of flowering plants or the role of bacteria of the genus Rhizobium in nitrogen fixation by leguminous plants are types of symbiotic relationships that have intrigued scientists. These happen to be examples in which both members of the association benefit, but that is not necessarily the case in symbiotic relationships. The word symbiosis simply means living together, and does not imply any advantage or disadvantage to either member of the partnership. Thus, we find that some fungi fulfill their needs by obtaining their nutrients from living hosts; i. There are some species that are obligate parasites in that they cannot survive and grow away from the living host, and there are others that may obtain their nutrients both from living hosts and by saprophytic means. Parasitism by the fungus is at the expense of the host, and while some hosts may be able to tolerate a certain amount of fungal growth, this kind of symbiotic relationship may bring about disease and even death of the host plant. Sometimes only one partner benefits and the other is not affected either beneficially or adversely, in which case the term commensalism is sometimes used. Chaetomium thermophile has strong cellulase activity, breaking down cellulose into cellobiose and glucose. Humicola, on the other hand, does not have strong cellulase activity, and it is thought that it utilizes the glucose made available by the cellulase activity of Chaetomium for its own growth needs. Thus, Humicola benefits from the presence of Chaetomium, which is not harmed in the process. There is some suggestion that this may be more a case of mutualism than commensalism because Chaetomium may also benefit by the removal of glucose. Glucose, an end product of the cellulase activity, slows the rate of action of the enzyme, so the removal of glucose would make for better cellulase activity by Chaetomium. This is, however, just another example of a situation in which systems in nature do not always fit perfectly into human-made categories. Lichens A lichen is a distinct organism that is made up of two components: (1) the algal component is known as the phycobiont and generally consists of a green or blue-green alga; (2) the fungal component is known as the mycobiont and most commonly consists of an ascomycete although there are some in which the mycobiont is a basidiomycete. Study of the conditions ж nutritional, physical and physiological ж that are required for the development of a lichen has indicated the close, mutualistic association of the algal and fungal components. Mycorrhiza Once thought to be rare and something of a biological oddity, it is now known that the association of fungi with the roots of plants, which is known as a mycorrhizal association, is very usual and takes place with most taxa of plants. This association of fungi with roots is an example of mutualism and is of special importance with certain edible fungi. There are a number of important edible Overview of the Biology of Fungi 89 fungi that are mycorrhizal fungi. While the mycelium of mycorrhizal fungi can be grown saprophytically, the formation of fruiting bodies is a product of the interaction of the fungus with the roots of a particular plant or group of plants; until the details of these interactions are discovered, the ability to control the fruiting of these mycorrhizal fungi will elude us. It is interesting that the edible species of mycorrhizal fungi include some of the most highly valued ones. These fungi belong to the type of mycorrhiza known as ectotrophic, in which the fungi form a sheath around the root with hyphae penetrating slightly into the root cortex. In ectotrophic mycorrhiza the hyphae grow between the cells of the root cortex, whereas in endotrophic mycorrhiza (also called vesicular arbuscular mycorrhiza) the hyphae form swollen or branched structures within the root cells. The endotrophic mycorrhizas do not form a sheath as is the case with ectotrophic mycorrhiza, and they are zygomycetes that are commonly associated with herbaceous plants.

Malarone is a widely used fixed combination tablet of proguanil hydrochloride with atovaquone medications that cause hyponatremia buy 40mg pepcid otc. Other prophylactic strategies Nets impregnated with permethrin offer substantial night-time protection medicine song buy generic pepcid 20 mg line. In pregnancy: Malaria can be a devastating disease during pregnancy symptoms nasal polyps safe 20 mg pepcid, and prophylaxis with proguanil is known to be of considerable value in areas where infection is endemic medicine 5113 v generic pepcid 20mg amex. Side effects are minimal with the standard prophylactic dose (200 mg once a day) medications dispensed in original container buy pepcid 20mg online, and there is no evidence of teratogenicity medications in spanish discount pepcid 20 mg visa. More needs to be learnt about maternal use during lactation medicine definition buy discount pepcid 40 mg on-line, but use certainly exposes the baby to much less drug than would result from standard prophylactic treatment (5 mg/kg once a day) medications cause erectile dysfunction order 40 mg pepcid with amex. Less is known about combined use with atovaquone, one retrospective study suggests that it is not a major teratogen, and most would argue that the combination should only be employed if no other alternative is available. In infancy: Start giving Malarone once a day 1­2 days before entering any area where malaria is prevalent and continue treatment for 1 week after leaving. It is probably safe to give children weighing at least 6 kg half of one paediatric tablet (i. Prophylaxis Treatment One option is to give any small child with overt signs of infection two crushed tablets of the paediatric strength Malarone once a day for 3 days. Supply Proguanil: Scored 100 mg tablets (which only cost 9p) can be quartered, crushed and administered on a spoon or down a nasogastric tube. Proguanil with atovaquone: Malarone provides an alternative approach to prophylaxis and treatment, but the manufacturers have not yet recommended prophylactic use in early infancy. The standard paediatric tablet (which may be crushed and mixed with food or milky drink) contains 25 mg of proguanil hydrochloride, and 62. The pharmacokinetics of atovaquone and proguanil in pregnancy in women with acute falciparum malaria. Randomised placebo-controlled study of atovaquone plus proguanil for malaria prophylaxis in children. A systematic review and meta-analysis of the effectiveness and safety of atovaquone-proguanil (Malarone) for chemoprophylaxis against malaria. Adults needing intensive care are often sedated with a continuous infusion, but serious (sometimes lethal) metabolic complications were encountered when this strategy was used in children. It is unrelated, chemically, to any other anaesthetic agent but behaves rather like ketamine (q. The elimination half-life in older children is 5­10 hours although, with sustained use, elimination from deep stores may take 2­3 days. In neonates, propofol mainly undergoes hydroxylation to quinol metabolites with only limited glucuronidation. Clearance in neonates is ~32% that in 1-year-olds, and while there is some general correlation between clearance and both post-menstrual and postnatal age, there is considerable inter-individual variability. Propofol crosses the placenta readily but is neither teratogenic nor fetotoxic in animals. The manufacturers do not recommend use during pregnancy or delivery, although it is used during caesarean section. It was thought to be the cause for green discolouration of breast milk in one woman. There is significant inter-individual variability in the pharmacokinetics of propofol in neonates, and its use has led to transient decreases in heart rate and oxygen saturation and more prolonged (60 minutes) hypotension even in what might be considered standard doses in older children. The drug was used as a sedative in paediatric intensive care for 15 years before any controlled trials were undertaken, and it was several years before reports of unexpected metabolic acidosis, and rhabdomyolysis, with sudden life-threatening cardiac and renal failure started to appear. It is now clear that prolonged infusion can sometimes cause a myopathy due to impaired fatty acid oxidation in patients of any age which is only reversible by stopping treatment at once and offering prompt haemoperfusion. Maintaining a generous glucose infusion may make this hazard less likely by limiting the tendency of the body to mobilise energy stores from fat. The addition of a 3 micrograms/kg bolus of remifentanil can be used to provide pain-free working conditions within 90 seconds, but this can cause brief apnoea, and intubation on its own should cause relatively little pain. Evidence suggests that this should never be given to any young child at a rate exceeding 4 mg/kg/hour. Where (as is often the case) this fails to provide adequate pain relief, an opiate, such as remifentanil, should be given as well ­ the dose of propofol should not be increased. Precautions Propofol use must be supervised by an experienced anaesthetist/intensivist, and recovery monitored until it is complete. This may be administered undiluted or diluted to a concentration not <1 mg/ml with 5% glucose or 0. The lipid content makes it important to protect any line used for sustained infusion from microbial contamination. Inter-individual variability in propofol pharmacokinetics in preterm and term neonates. Propofol compared with the morphine, atropine, and suxamethonium regimen as induction agents for neonatal endotracheal intubation: a randomized, controlled trial. Sedation and analgesia for brief diagnostic and therapeutic procedures in children. Combined propofol and remifentanil anesthesia for pediatric patients undergoing magnetic resonance imaging. Pharmacology Propranolol hydrochloride was the first non-selective -adrenoreceptor blocking agent. It reduces the rate and force of contraction of the heart and slows cardiac conduction. The hypotension and bradycardia seen with an overdose are best treated with glucagon (q. The half-life in children and adults is 3­6 hours; the neonatal half-life is substantially longer at 14­15Ѕ hours. Propranolol has been used extensively during pregnancy for the treatment of maternal hypertension, arrhythmia and migraine headache. Use during the second and third trimesters has been associated with fetal growth restriction, and the exposed fetus may display signs of -blockade after delivery. Propranolol passes into breast milk in small amounts that do not cause any clinically significant effects in the breastfed infant. Neonatal problems are most frequently seen in babies of mothers with a high antibody titre. This can occur even after the mother has been rendered medically or surgically euthyroid. Lugol iodine (which contains 130 mg/ml of iodine) provides the most easily obtained source of iodine for inhibiting thyroid function. Always seek the advice of an experienced paediatric endocrinologist if symptoms are severe. Infantile haemangiomas Infantile haemangiomas are the most common vascular tumours of childhood and affect ~5% of all infants. Although most proliferate and then spontaneously involute with minimal consequences, a small minority can be disfiguring, functionally significant or, rarely, life-threatening. Until recently, corticosteroids were the mainstay of treatment, but these are not without side effects. Systematic review of 41 of these studies showed a response rate, defined as an improvement after starting treatment, of 98% (range 82­100%). Given that many would involute anyway, it is easy to be sceptical; however, evidence from one small randomised trial supports the fact that propranolol speeds the natural resolution, at least in infants. Although propranolol seems efficacious, side effects are cause for concern in some infants; these include symptomatic hypoglycaemia, hypotension, wheeze and bronchial hyperreactivity, seizure, restless sleep and constipation. For this reason, and the benign outcomes of conservative management, propranolol is best reserved for those haemangioma that are likely to cause problems. Treatment Neonatal thyrotoxicosis: Give 250­750 micrograms/kg every 8 hours by mouth to control symptoms, with one drop of Lugol iodine every 8 hours to control the transient neonatal thyrotoxicosis. For sustained oral maintenance, try 250­500 micrograms/kg every 8 hours, adjusted according to response to a maximum of 1 mg/kg every 8 hours. Neonatal hypertension: Start with 250 micrograms/kg every 8 hours by mouth together with hydralazine (q. Infantile haemangiomas: the target dose for treatment is 1­3 mg/kg/day in three divided doses. Begin with the lowest possible dose and titrate upwards according to the response; many haemangiomas will respond to even small doses. Blood levels the therapeutic blood level in adults is said to be 20­100 mg/l (1 mg/l = 3. Propranolol is available as an oral solution in several strengths (1 ml may contain 1, 2, 4 or 10 mg). Initiation and use of propranolol for infantile hemangioma: report of a consensus conference. Propranolol concentrations after oral administration in term and preterm neonates. Efficacy and safety of intravenous and oral nadolol for supraventricular tachycardia. Respiratory depression and apnoea are common with high-dose treatment (some texts still recommend a dose that is much higher than necessary) and may occur, even with the dose recommended here, especially in the cyanosed or preterm baby. High-dose treatment causes vasodilatation and hypotension and has rarely caused diarrhoea, irritability, seizures, tachycardia, pyrexia and metabolic acidosis. Sustained oral administration is still sometimes used, but it is rarely employed because delay is not thought to render surgery any less technically difficult. Some babies manage with treatment every 3­4 hours, but many need a dose every 2 hours to remain stable. Maternal: 1 mg of vaginal gel (2 mg if the cervix is unfavourable) inserted high into the posterior fornix, or a 3 mg vaginal tablet similarly positioned is now the most widely used method of inducing labour. Always aim to use the lowest effective dose ­ a dose as high as 40 nanograms/kg/ minute is very rarely necessary. Note: 10 mg/ml ampoules are sometimes stocked for use in termination of pregnancy. Vaginal gels and tablets are widely used to induce labour; the two are not strictly bioequivalent. References (See also the Cochrane reviews of obstetric use) Brodie M, Chaudari M, Hasan A. Transporting newborn infants with suspected duct dependent congenital heart disease on low-dose prostaglandin E1 without routine mechanical ventilation. Prostaglandin E1 use during neonatal transfer: potential beneficial role in persistent pulmonary hypertension of the newborn. Persistent pulmonary hypertension of the newborn successfully treated with beraprost sodium: a retrospective chart review. Antenatal steroids and exogenous pulmonary surfactants (of synthetic and animal origin) have improved the outcomes in preterm babies considerably since they became more widely used. The lung of the very preterm baby may contain as little as 10 mg/kg of surfactant at birth (a 10th of the amount at term). While labour and/or birth triggers a surge of endogenous surfactant, this takes 48 hours to become fully effective. Care needs to be exercised during this time, as both acidosis and hypothermia interfere with this process, while alveolar collapse increases surfactant consumption. The development of artificial and natural products to bridge this time gap, and their rigorous evaluation, has been one of the major achievements of neonatal medicine. Endogenous surfactant has a half-life of about 12 hours, after which some is recycled and some is degraded. The baby who is deficient at birth, therefore, needs to be given 100 mg/kg as soon as possible to prevent atelectasis (alveolar collapse) from developing, and if destruction initially exceeds production, one (and occasionally two) further dose 12 and 24 hours later. It is now widely accepted that if non-invasive respiratory support can be provided for babies who are surfactant deficient at birth, this will reduce the numbers of babies with chronic oxygen dependency. The more vulnerable babies may also benefit from early surfactant, but everything should be done to minimise the need to provide ongoing respiratory support using a tube through the larynx. Indications for use Trials conducted in the current era of non-invasive ventilation for respiratory support suggest that there is no particular merit in planning intubation for prophylactic surfactant treatment. The cost of treating babies more mature than this is harder to justify until it is clear that they need >40% oxygen to sustain an arterial PaO2 above 7 kPa (or 90% SaO2). Babies needing ventilation for pneumonia or meconium aspiration merit consideration for treatment with a product containing surfactant proteins (see web commentary). Give a second dose (100 mg/kg) after 4­6 hours if the baby continues to need ventilation with a mean airway pressure of >7 cm H2O and >40% oxygen, or if there are signs of pneumonia. Consider giving a smaller first dose of 100 mg/kg if surfactant is being given prophylactically in delivery suite, for example, in extremely preterm infants for whom there has not been time to receive antenatal steroids. Beractant: Give 100 mg/kg (4 ml/kg) in the same way as for poractant alfa but in two to three aliquots. The manufacturer says up to three further doses can be given, at least 6 hours apart, within the next 48 hours. Treatment Optimising usage Surfactant treatment can be very cost-effective but remains expensive, and a lot can be done to limit redundant and unnecessary treatment. If the lung disease is more severe, there is much to recommend giving subsequent doses of surfactant earlier than the manufacturers recommend. It is traditional to instil the prescribed dose down an endotracheal tube using a fine catheter with the baby supine after clearing any mucus and pre-oxygenating the lungs to minimise cyanosis during administration. For many years, it was assumed that if surfactant was required, then the baby would need both intubation and sustained respiratory support ­ neither of these assumptions is necessarily correct. It is widely thought that giving the appropriate dose of surfactant in a small volume of fluid will cause fewer cardiovascular disturbances, but a larger volume leads to a more even dispersal within the lung. Surfactant can be given in less than a minute (rather than 4 minutes, as manufacturers often recommend) without causing bradycardia or cyanosis. Natural surfactants increase lung compliance and oxygenation rapidly ­ be prepared to reduce the ventilator settings and, more especially, the amount of oxygen quite soon after they are given. Beractant comes in 8 ml vials containing 200 mg of phospholipid which cost Ј310; 4 ml (100 mg) vials are also available in some countries. Store vials at 4 °C, but warm to room temperature before use, and invert gently without shaking to resuspend the material. Do not use, or return vials to the refrigerator, more than 8 hours after they reach room temperature. References (See also the relevant Cochrane reviews) Broadbent R, Fok T-F, Dolovich M, et al. Chest position and pulmonary disposition of surfactant in surfactant depleted rabbits. Continuous positive airway pressure therapy for infants with respiratory distress in non-tertiary care centers: a randomized controlled trial. Minimally-invasive surfactant therapy in preterm infants on continuous positive airway pressure. High- versus low-threshold surfactant retreatment for neonatal respiratory distress syndrome. Animal-derived surfactants versus past and current synthetic surfactants: current status. Clinical report: surfactant replacement therapy for preterm and term neonates with respiratory distress. Unexplained neonatal respiratory distress caused by congenital surfactant deficiency. European consensus guidelines on the management of neonatal respiratory distress syndrome. European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants­2013 update. A randomized, controlled trial of delivery-room respiratory management in very preterm infants. Surfactant replacement in spontaneously breathing babies with hyaline membrane disease ­ a pilot study. To minimise the risk of drug resistance developing, management should always be overseen by a clinician with substantial experience of this condition. The half-life in adults is 9­10 hours, but it does not seem to have been studied in children. Excretion is impaired in severe renal failure, but drug accumulation does not occur during peritoneal dialysis. Liver toxicity is the main hazard, so liver function should be checked before treatment is started and repeated at intervals if there is pre-existing liver disease. Review treatment at once if any sign of liver toxicity (such as nausea, vomiting, drowsiness or jaundice) develops during treatment. Manufacturers in the United States have endorsed use in children, but no such move has been made in the United Kingdom. Pyrazinamide passes into breast milk in small amounts that are unlikely to be of clinical significance in the breastfed infant. Give the baby 5 mg/kg of isoniazid as chemoprophylaxis once a day for 3 months, and then do a Mantoux test. Give a further 20 weeks of isoniazid if this is positive or if the interferon gamma test is positive (where facilities exist for performing this test). Treatment is a two-stage process ­ an initial 2-month phase using three (or even four) drugs designed to reduce bacterial load to a minimum and minimise the risk of drug resistance developing and a 4-month maintenance phase using just two drugs. Pyrazinamide: Give 35 mg/kg of pyrazinamide by mouth once a day for the first 2 months of treatment. It is critically important to ensure that the dose is correct and that treatment is taken every day as prescribed. There is a very real risk that dangerous drug-resistant bacteria will evolve and put both the patient, and the community, at risk if this is not done. A 15 mg/kg dose of ethambutol given once a day for 2 months is the most commonly employed option.

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Biological systems can now be studied dynamically through measurement of the activation or suppression of genes and metabolic pathways; the study and characterization of the circuitry involved in biological systems over time is called systems biology medicine daughter cheap pepcid 20 mg on line. The concepts of systems biology and their application to medicine are allowing the evolution of disease to be characterized and are making it possible to predict and track its development [8 medical treatment 80ddb buy 40 mg pepcid with mastercard, 13 medicine doctor cheap 40 mg pepcid free shipping, 14] symptoms xeroderma pigmentosum best pepcid 20mg. The concept that diseases result from the exposure of a host to a causative factor is too simplistic medications that cause constipation pepcid 20mg low price. Although the tubercle bacillus may be the "cause" of tuberculosis medicine quinine buy 40mg pepcid fast delivery, the underlying health of the individual treatment west nile virus discount 40 mg pepcid free shipping, his or her inherited figure 1 treatment renal cell carcinoma pepcid 20mg free shipping. The sciences of the early 20th century enabled the identification of many disease mechanisms and causative factors. The science and technologies of the 21st century are enabling a dynamic understanding of health, the development of chronic diseases, and personalized health care. Disease may be initiated by a specific factor, such as a microbe or a toxin, or it may result from exposure to complex environmental factors, including diet, exercise, and stress. The reductionist approach to medicine unwittingly led to a disease-based health care system, but the systems biology approach, which recognizes the complexity of disease development, enables a dynamic and personalized health care model. Personalized health care is proactive, accounts for the unique characteristics of the individual, and fosters enhancement of health as well as minimization of disease [4, 5, 7, 8, 10, 11]. Genetics and genomics provide an important scientific foundation for personalized health care. Personalized Health Care and the Role of Genomics Personalized health care is an approach to medicine that combines the concepts of systems biology, genomics, and other predictive technologies to create care that encourages patient participation and is personalized, predictive, and figure 2. Disease develops over time, and pathology accumulates subclinically until an initial clinical event signals its presence. As disease progresses, the cost of treatment increases and reversibility decreases. Available and emerging technologies enable early quantification of risk, measurement of disease progression, and early targeted intervention. Although many common diseases are based on Mendelian inheritance (eg, sickle-cell anemia, hemophilia, cystic fibrosis, Huntington disease), susceptibility to most chronic diseases results from more complex genetic inheritance [15-17]. With this in mind, we can envision an approach to health enhancement and disease prevention or minimization that is based on how diseases actually develop. These concepts are the underlying basis of personalized health care, and the importance and limitations of genomics become apparent when viewed in this context. Genomic analysis can aid in the prediction of baseline risks for certain diseases and may be able to help predict the course of disease [11]. This can be achieved by sequencing the whole genome or the exome and analyzing specific disease-associated variants, or by gathering information about which genes or gene products are specifically activated or suppressed in tissues of clinical interest [15, 20]. Baseline genetic analysis provides static background information regarding risk, whereas measurement of gene activation evaluates current activities. Genomics can also help to diagnose some diseases more precisely and can help to guide treatment. Thus genomics provides an important series of capabilities that allow personalized health care to continuously improve as technologies and clinical data provide more information. Personalized health care is a coordinated, strategic approach to patient care that employs health care planning and appropriate predictive technologies-including, but not limited to , genomics-to customize care delivery across a continuum from health promotion to disease management. Prospective health care and P4 medicine (predictive, personalized, preventative, and participatory medicine) are terms used in the description of personalized health care [8, 23]. A personalized health plan is a customized health plan that the provider and the patient develop together. It is a tool for coordinating and managing care for a distinct purpose (eg, health enhancement, primary prevention, or disease management). Progress is monitored by biomarkers or tracking tools that are incorporated into a therapeutic plan that is agreed upon by the patient and the provider. Personalized medicine is the application of personalized medicine tools, whether genomic or not, to medical care. Nongenomic prediction tools include the Framingham coronary heart disease risk score and the Gail model for assessing the risk of breast cancer [10]. Precision medicine is the use of the full range of predictive technologies, including information from large databases, to diagnose and treat individual diseases. The terms personalized medicine and precision medicine are often used interchangeably [24]. Genomic medicine is often incorrectly equated with personalized medicine, which has a broader definition. Genetic testing has already added to the value of newborn screening and has improved prediction of susceptibility to cancer, coronary artery disease, and other illnesses, and the impact of genetic testing on the practice of medicine will certainly increase in the future [15, 18, 19, 25]. Status of Genomics and Related Technologies in Personalized Health Care Genomics and related testing, including gene expression and proteomic analysis, facilitate the personalization of health care in a number of ways. Specifically, such testing may make it possible to predict clinical risks, to diagnose disease, to identify disease mechanisms, to detect targets for individualized therapy, to track response to therapy, to pre- figure 3. Decision Tree Showing the Elements of a Personalized Health Care Plan for Treatment of a Disease Note. Personalized health planning can be thought of as a complex decision tree in which an initial clinical evaluation identifies goals to be met by subsequent therapeutic approaches (Figure 3). Based on the initial evaluation, diagnoses are considered and refined by further testing. In addition to providing a large array of diagnostic tools, genomic testing may be able to offer a far more precise diagnosis and definition of disease mechanisms and clinical risks. Similarly, genomic analyses can refine therapy selection on a mechanistic basis, help identify doses for certain therapies, and predict severe adverse outcomes. Once a therapeutic approach is undertaken, genomics and other predictive tools can help to track the progress of therapy and to inform new or additional therapeutic approaches (Table 1). The ability of genomics to add value to clinical care is dependent not only on the technology used to sequence genes but also on our understanding of the role of genetic variations in health and disease. The Human Genome Project, which was launched in 1990, enabled a new understanding of biology, evolution, anthropology, and definition of disease; it also identified therapeutic targets [15-17]. When Frederick Sanger first introduced gene sequencing in 1977, it allowed analysis by electrophoresis of approximately 102 channels at a time. Today, new optical methods allow roughly 109 templates to be measured simultaneously [16]. The cost of whole-genome sequencing has plummeted from more than $100 million in 2000 to about $5,000 today, and some predict that it may drop as low as $1,000 in the future [15]. Critical to understanding the impact of gene sequences on clinical manifestations is identifying haplotypes-genetic variants at a single locus reflecting linkage disequilibrium- and relating them to clinical manifestations. Capabilities and Tools Needed for Personalized Health Planning Capability needed To quantify health risks Personalized medicine tools providing that capability Health risk assessments Genomic predictors Single-nucleotide polymorphisms Gene sequencing Gene expression Biomarkers Gene expression tests Proteomics tests Metabolomic profiles Clinical risk models Clinical decision support Adverse outcome models Drug metabolism indicators Companion diagnostics Targeted therapies To monitor disease progression To define disease mechanisms To select appropriate therapies that disease. Direct-to-consumer testing for disease-susceptibility variants uses this technology [26, 27]. Microarray technology analyzes messenger ribonucleic acid from tissues, and gene expression patterns are identified. Complex algorithms can be developed to determine the relationship between patterns of gene activation and specific clinical issues, such as tumor aggressiveness, the likelihood of graft rejection, or the need for cardiac angiography [15]. ApplicationsofGenomicstoPersonalizedHealth Care Genomic analysis can be used to identify specific genetic variants associated with disease or disease risk. Newborn screening for inherited Mendelian diseases, such as phenylketonuria and other metabolic disorders, has been available since the 1960s. As Sparks explains in her commentary [18], many newborn screening and diagnostic tests do not rely on genomics, but genomic technologies are nonetheless improving the clini- cal value of newborn screening. Prenatal screening in utero has also been greatly enhanced by genomic technologies, as Dickerson discusses in her commentary [19]. A major hope for the Human Genome Project was that whole-genome sequencing would lead to an understanding of the genetic basis of complex common diseases such as coronary artery disease, type 2 diabetes, and common psychiatric disorders. The goal of such studies is to identify common variants associated with diseases; these studies are based on the premise that approximately 99% of genetic variance is due to common variants. For common diseases, many susceptibility alleles would be expected to have a small but ultimately important impact on disease development. In each case, many loci have been identified, each contributing a small amount of risk, and studies have begun to improve our understanding of the underlying disease pathways [15-17]. In their commentary discussing genetic testing and obesity, Ng and Bowden [28] explain that genetic predisposition may play a role in the development of obesity; understanding this role could inform the treatment approach for specific individuals. Whole-genome sequencing has already produced an abundance of apparently incidental findings that may have no clinical utility. In a sidebar, Krantz and Berg discuss how crowdsourcing can be used to determine the clinical relevance of incidental findings [29]. Genomic technologies have already begun to revolutionize approaches to cancer care by evaluating the clinical risks of breast cancer or helping to select targeted therapy. By defining the molecular pathways driving tumor growth, genetic technologies have identified drug targets, particularly protein kinases, and drugs that are able to specifically inhibit such drivers of disease are offering exciting new therapies for many forms of cancer. The ability to identify targets for therapies and to design diagnostic tests to detect the patients who are likely to respond to targeted therapy is revolutionizing cancer and its treatment (Table 2) [30, 31]. Genomic tests can also be useful in evaluating disease activity and aggressiveness and can thereby help to inform therapy. The tools derived from this understanding and the adaptation of such tools to the practice of medicine will continue to improve the power of personalized health care. Direct-to-Consumer Testing Many consumers have an interest in understanding their inherited disease risks. Although the accuracy of the measurements has not been problematic, the determination of disease susceptibility and the practical meaning of results have been troublesome, because we lack sufficient clinical data to allow for predictive validation [15]. These issues are discussed in the commentary by Adams and colleagues [26] and in the sidebar by Gulisano [27]. Despite the unexpected difficulty of developing practical gene therapies, progress is being made-as Porada and colleagues discuss in their commentary [32]-and gene therapy is seen as a hope for curing many of the perhaps 10,000 human diseases that are caused by defects in a single gene. Pharmacogenomics, which enables the identification of variations in drug metabolism as a consequence of inheritance, is discussed in detail by Jonas and Wines in their commentary [33]. Genomic research has begun to have an impact on medical care, to reveal the genetic basis of susceptibility to common diseases, and to better define disease mechanisms. The full impact of this research on clinical practice remains to be seen, but systems biology approaches-with nextgeneration sequencing, additional clinical studies (including observational studies), massive databases, and state-ofthe-art bioinformatics-are expected to help revolutionize Ethical, Social, and Policy Issues Facing Genomic Medicine To realize the full value of genomics for improving health care, major technical hurdles must be overcome so that we can validate the use of such technologies to accurately predict clinical outcomes. Clinical validation of genomic or other predictive tools often requires that vast amounts of data from many sources be aggregated and analyzed over a long period of time. Resolving ethical, social, and policy issues is at least as important as overcoming technical hurdles. In her commentary, Tong explores the boundaries between personalized medicine and public health and explains the frameworks involved in genetic testing and treatment [35]. Other matters that need to be addressed are discussed by Dressler in her commentary [36]; these include how genomic tools are validated, what role the consumer plays in accessing genetic information, who pays for genetic tests, how providers and patients are educated to interpret genetic information, who owns genes or genetic information, and who has the right to access personal genetic information. Genomic and personalized medicine tools make possible a new approach to the practice of medicine. However, physicians and other health care providers must be trained and supported in this prospective approach to care; such training is discussed in the sidebar by Katsanis and colleagues [37]. The availability of clinical infrastructure-including electronic medical records, clinical decision support tools, and clinical training regarding the utility of genetics-will be essential. Reimbursement, patient privacy protection, and public acceptance also will need to be addressed to allow for full implementation [15, 35-37]. To sum up, genomics has already begun to affect health care, particularly by providing more accurate diagnoses and by identifying targets for therapy and selective therapeutics. Equally important, genomics can enhance our understanding of who we are, where we came from, and, to a degree, where we are going. Many issues must be resolved in order to fully unleash the practical applications of genomic research, but the future will be exciting. Duke Professor of Medicine, Duke University Medical Center; and director, Duke Center for Research on Prospective Health, Durham, North Carolina. Acknowledgments the author gratefully acknowledges the invaluable support of Cindy Mitchell and thanks her for her assistance in developing this manuscript. Medical Education in the United States and Canada: A Report to the Carnegie Foundation for the Advancement of Teaching. Genetic epidemiology: the potential benefits and challenges of using genetic information to improve human health. Personalized medicine is more than genomic medicine: confusion over terminology impedes progress towards personalized health care. Direct-to-consumer genomic testing offers little clinical utility but appears to cause minimal harm. Direct-to-consumer nutrigenomic testing: Is it valuable in spite of its limitations? Crowdsourcing to define the clinical actionability of incidental findings of genetic testing. Integrating personalized genomic medicine into routine clinical care: addressing the social and policy issues of pharmacogenomic testing. Jonas, Roberta Wines Pharmacogenomics offers the hope of greater individualization of treatment. Therapies that exemplify the promise of pharmacogenomics include anticoagulation with warfarin andtheuseofantiplateletmedications(eg,clopidogrel)for secondary prevention after acute coronary syndrome. Good evidence of clinical utility must be obtained before pharmacogenomic testing is widely implemented. Clopidogrel and other oral P2Y12 inhibitors (eg, ticagrelor and prasugrel) are commonly used for secondary prevention after acute coronary syndrome. Warfarin In the United States, more than 30 million prescriptions are written for warfarin each year [3, 4], and of all the drugs in the modern medical formulary, warfarin remains one of the most challenging to manage. It is consistently one of the leading causes of adverse drug reactions leading to emergency department visits and hospitalizations, both in the United States and worldwide [5], and there are an estimated 7. Warfarin has a narrow therapeutic window: Doses that are slightly too high can result in catastrophic hemorrhagic complications, whereas doses that are too low can result in thrombotic complications. This finding has been replicated in observational studies of populations around the world [9, 10]. Several dose-calculation algorithms that combine clinical factors and genotypic information have been shown to accurately predict warfarin doses. In retrospective studies of patients receiving long-term therapy with stable doses Electronically published November 19, 2013. In addition, when several medication options are available, pharmacogenomics could help us choose the one most appropriate for a particular individual. Scientific advances in genome sequencing have resulted in a number of predictive genetic tests that are potentially useful for health care decision making. For many practicing clinicians, the field of genomics is a "black box" plagued by uncertainty, hype, direct-to-consumer marketing, and little evidence of clinical utility. Many clinicians do not have the time or the tools to evaluate pharmacogenomic tests, and these tests are challenging to evaluate even for those who have a relatively detailed knowledge of genetics and related concepts [2]. Two types of drug therapy that exemplify the promise of pharmacogenomics are anticoagulation with warfarin and the use of antiplatelet medications for secondary prevention after acute coronary syndrome. Warfarin is widely used to treat people with atrial fibrillation, deep venous thrombosis, pulmonary emboli, or artificial heart valves. It is a multisystem disease with morbidity and mortality resulting primarily from progressive pulmonary disease. This protein is an ion channel that regulates the movement of chloride and bicarbonate, and abnormalities in this protein can lead to problems with the secretion of salt and water in a variety of tissues. These genetic mutations can be separated into 5 categories, referred to as classes [1, 2]. The defective protein produced by class 2 mutations is recognized as misfolded and is quickly degraded; thus it never reaches the cell membrane. Class 3 mutations cause defective protein regulation, often by means of reduced chloride channel activity. Despite this finding, randomized controlled trials have not yet shown that genotype-guided warfarin dosing improves clinical outcomes [11-14]. Having good evidence of clinical utility prior to widespread implementation of pharmacogenomic testing is important duced in number. With these separate classes of genetic mutations, multiple opportunities have arisen to target the specific disease process. Using high-throughput screening libraries, pharmaceutical companies have been able to identify numerous candidate compounds that can target specific mutations. Potentiators promote effective chloride transport and can prolong opening of chloride channels. Potentiators do not correct protein folding or transcription; rather, they target mutations that impair the function of a protein product that is already on the cell surface (Class 3, 4, or 5 mutations); in contrast, correctors are used to address mutations that result in protein products being trapped within the cell (Class 1 or 2). Subjects receiving ivacaftor were 55% less likely to have pulmonary exacerbations than those receiving placebo [3], and those receiving ivacaftor also gained more weight [3, 4]. Two other molecules that have been under study also fall into the category of correctors. First, promoting the use of a test without evidence of clinical utility can be damaging for the field of pharmacogenomics; if the test is eventually shown not to be clinically useful, providers may become more skeptical of pharmacogenomic testing in general, which could substantially slow implementation of future tests that truly are useful. Second, time is a scarce resource for providers [16, 17], and a better alternative use of resources (ie, physician time, patient time, and reimbursements) would be to direct them toward things that have already been shown to have clinical utility- for example, screening for colorectal cancer or screening and behavioral interventions for unhealthy alcohol use. Third, innovation and rapid diffusion of technology is a significant contributor to the high and rising cost of health care [18]. Indiscriminate dissemination and implementation of tests without evidence of clinical utility and cost effectiveness will further contribute to this problem. On later investigation, researchers found that aminoglycosides such as tobramycin, a medication that is commonly prescribed for cystic fibrosis, can interfere with ataluren at the ribosome [9]. In summary, cystic fibrosis is providing proof of concept that personalized medicine can be used to correct the base pathophysiology of a disease. Ivacaftor is the first drug of its kind to directly target the specific protein misfolding that leads to reduced activity of a protein. In the near future, physicians who treat patients with cystic fibrosis hope to add other medications to their arsenal that can directly combat the underlying defect of the disease. Thus, for any given mutation carried by a cystic fibrosis patient, we will have a drug aimed at that specific mutation.

Because both cabbage and radish possess 18 chromosomes treatment quinsy buy 40mg pepcid with visa, Karpechenko was able to successfully cross them treatment yellow jacket sting buy pepcid 20 mg low cost, producing a hybrid with 2n = 18 medications osteoporosis buy 40 mg pepcid with visa, but symptoms blood clot leg order pepcid 40 mg mastercard, unfortunately medicine 44-527 40 mg pepcid with mastercard, the hybrid was sterile medicine joint pain buy 20mg pepcid free shipping. After several crosses treatment restless leg syndrome purchase pepcid 20mg amex, Karpechenko noticed that one of his hybrid plants produced a few seeds medications blood thinners generic pepcid 20 mg overnight delivery. Analysis of their chromosomes revealed that the plants were allotetraploids, with 2n = 36 chromosomes. Give all possible chromosome numbers that may be found in the following individuals. A common mistake is to assume that 3n means three times as many chromosomes as in a normal individual, but remember that normal individuals are 2n. Because n for species I is 7 and all genomes of an autopolyploid are from the same species, 3n = 3 Ч 7 = 21. By definition, an allotetraploid must have genomes from at least two different species. Thus, the increase in chromosome number in polyploidy is often associated with an increase in cell size, and many polyploids are physically larger than diploids. Breeders have used this effect to produce plants with larger leaves, flowers, fruits, and seeds. The hexaploid (6n = 42) genome of wheat probably contains chromosomes derived from three different wild species (Figure 9. As discussed, allopolyploids require hybridization between different species, which happens less frequently in animals than in plants. Animal behavior often prevents interbreeding among species, and the complexity of animal development causes most interspecific hybrids to be nonviable. Many of the polyploid animals that do arise are in groups that reproduce through parthenogenesis (a type of reproduction in which the animal develops from an unfertilized egg). Thus, asexual reproduction may facilitate the development of polyploids, perhaps because the perpetuation of hybrids through asexual reproduction provides greater opportunities for nondisjunction than does sexual reproduction. Only a few human polyploid babies have been reported, and most died within a few days of birth. Polyploidy-usually triploidy-is seen in about 10% of all spontaneously aborted human fetuses. In many cases, existing copies of a gene are not free to vary, because they encode a product that is essential to development or function. However, after a chromosome undergoes duplication, extra copies of genes within the duplicated region are present. The original copy can provide the essential function, whereas an extra copy from the duplication is free to undergo mutation and change. Over evolutionary time, the extra copy may acquire enough mutations to assume a new function that benefits the organism. Inversions also can play important evolutionary roles by suppressing recombination among a set of genes. As we have seen, crossing over within an inversion in an individual Source: After F. Problems in chromosome pairing and segregation often lead to sterility in autopolyploids, but many allopolyploids are fertile. This suppression of recombination allows particular sets of coadapted alleles that function well together to remain intact, unshuffled by recombination. Polyploidy, particularly allopolyploidy, often gives rise to new species and has been particularly important in the evolution of flowering plants. Occasional genome doubling through polyploidy has been a major contributor to evolutionary suc- cess in animal groups. For example, Saccharomyces cerevisiae (yeast) is a tetraploid, having undergone whole-genome duplication about 100 million years ago. The vertebrate genome has duplicated twice, once in the common ancestor to jawed vertebrates and again in the ancestor of fishes. Certain groups of vertebrates, such as some frogs and some fishes, have undergone additional polyploidy. Duplications often have pronounced effects on the phenotype owing to unbalanced gene dosage. In individuals heterozygous for an inversion, the homologous chromosomes form inversion loops in meiosis, with reduced recombination taking place within the inverted region. These variants are common in the human genome; some are associated with diseases and disorders. Mosaicism is caused by nondisjunction in an early mitotic division that leads to different chromosome constitutions in different cells of a single individual. It is produced when the dominant wild-type allele in a heterozygous individual is absent due to a deletion on one chromosome. Dosage compensation prevents the expression of additional copies of X-linked genes in mammals, and there is little information in the Y chromosome; so extra copies of the X and Y chromosomes do not have major effects on development. In contrast, there is no mechanism of dosage compensation for autosomes, and so extra copies of autosomal genes are expressed, upsetting development and causing the spontaneous abortion of aneuploid embryos. A B C D E E D C · F G have changed; this mutation is therefore a pericentric inversion of region (B C D E · F). The mutated chromosome (A B C D E E D C · F G) contains a duplication (C D E) that is also inverted; so this chromosome has undergone a duplication and a paracentric inversion. Give the chromosomes that would be found in individuals with the following chromosome mutations. The mutated chromosome (A B E · F G) is missing segment C D; so this mutation is a deletion. The mutated chromosome (A E D C B · F G) has one and only one copy of all the gene segments, but segment B C D E has been inverted 180 degrees. Because the centromere has not changed location and is not in the inverted region, this chromosome mutation is a paracentric inversion. The mutated chromosome (A B A B C D E · F G) is longer than normal, and we see that segment A B has been duplicated. The mutated chromosome (A F · E D C B G) is normal length, but the gene order and the location of the centromere · Solution To work this problem, we should first determine the haploid genome complement for each species. A monosomic is missing a single chromosome; so a monosomic for species I would be 2n ­ 1 = 4 ­ 1 = 3. Sketch the chromosome pairing and the different segregation patterns that can arise in an individual heterozygous for a reciprocal translocation. Draw a pair of chromosomes as they would appear during synapsis in prophase I of meiosis in an individual heterozygous for a chromosome duplication. Explain, with the aid of a drawing, how a dicentric bridge is produced when crossing over takes place in an individual heterozygous for a paracentric inversion. Explain why recombination is suppressed in individuals heterozygous for paracentric and pericentric inversions. Explain why autopolyploids are usually sterile, whereas allopolyploids are often fertile. For each mutation, sketch how the wild-type and mutated chromosomes would pair in prophase I of meiosis, showing all chromosome strands. Draw the chromatids that would result from a two-strand double crossover between E and F in Problem 24. Maarit Jaarola and colleagues examined individual sperm cells of a male who was heterozygous for a pericentric inversion on chromosome 8 and determined that crossing over took place within the pericentric inversion in 26% of the meiotic divisions (M. Assume that you are a genetic counselor and that a couple seeks counseling from you. Both the man and the woman are phenotypically normal, but the woman is heterozygous for a pericentric inversion on chromosome 8. What is the probability that this couple will produce a child with a debilitating syndrome as the result of crossing over within the pericentric inversion? Diagram the alternate, adjacent-1, and adjacent-2 segregation patterns in anaphase I of meiosis. Give the products that result from alternate, adjacent-1, and adjacent-2 segregation. Female flies heterozygous for Notch have an indentation on the margins of their wings; Notch is lethal in the homozygous and hemizygous conditions. The Notch deletion covers the region of the X chromosome that contains the locus for white eyes, an X-linked recessive trait. The green-nose fly normally has six chromosomes, two metacentric and four acrocentric. A geneticist examines the chromosomes of an odd-looking green-nose fly and discovers that it has only five chromosomes; three of them are metacentric and two are acrocentric. Where did the nondisjunction that gave rise to the young man with Klinefelter syndrome take place? The disorder is caused by autosomal recessive mutations at any one of three loci that help to encode laminin 5, a major component in the dermal­epidermal basement membrane. American Journal of Human Genetics 61:611­619); the child had healthy unrelated parents. Assuming that no new mutations occurred in this family, explain the presence of an autosomal recessive disease in the child when the mother is heterozygous and the father is homozygous normal. On the basis of these observations, indicate which of the following statements are most likely correct and which are most likely incorrect. In mammals, sex-chromosome aneuploids are more common than autosomal aneuploids but, in fish, sexchromosome aneuploids and autosomal aneuploids are found with equal frequency. A chromosome analysis reveals that, whereas the woman has a normal karyotype, the a. What types of zygotes will develop when each of gametes produced by the man fuses with a normal gamete produced by the woman? If trisomies and monosomies entailing chromosomes 13 and 22 are lethal, what proportion of the surviving offspring will be carriers of the translocation? Oxford: Oxford University Press, Clarendon Press; New York: Oxford University Press, 1987) created mice that were trisomic for each of the different mouse chromosomes. For some of these trisomics, they compared the length of development (number of days after conception before the embryo died) as a function of the size of the mouse chromosome that was present in three copies (see the adjoining graph). Summarize their findings as presented in this graph and provide a possible explanation for the results. How many chromosomes will be found per cell in each of the following mutants in this species? What types of chromosome mutations do individual organisms with the following sets of chromosomes have? What would the expected chromosome numbers be in individual organisms with the following chromosome mutations? Consider a diploid cell that has 2n = 4 chromosomes- one pair of metacentric chromosomes and one pair of acrocentric chromosomes. Suppose this cell undergoes nondisjunction giving rise to an autotriploid cell (3n). Draw the different types of gametes that may result from meiosis in the triploid cell, showing the chromosomes present in each type. To distinguish between the different metacentric and acrocentric chromosomes, use a different color to draw each metacentric chromosome; similarly, use a different color to draw each acrocentric chromosome. They were able to self-pollinate the flowers of this plant to produce an F2 generation. What would be the chromosome number of progeny resulting from the following crosses in wheat (see Figure 9. Einkorn wheat and emmer wheat Bread wheat and emmer wheat Einkorn wheat and bread wheat Karl and Hally Sax crossed Aegilops cylindrica (2n = 28), a wild grass found in the Mediterranean region, with Triticum vulgare (2n = 42), a type of wheat (K. Examination of metaphase I in the F1 plants revealed the presence of 7 pairs of chromosomes (bivalents) and 21 unpaired chromosomes (univalents). If the unpaired chromosomes segregate randomly, what possible chromosome numbers will appear in the gametes of the F1 plants? What does the appearance of the bivalents in the F1 hybrids suggest about the origin of Triticum vulgare wheat? James and Margaret Lesley observed that secondaries arise from triploid (3n), trisomic (3n + 1), and double trisomic (3n + 1 + 1) parents, but never from diploids (2n). Give one or more possible reasons that secondaries arise from parents that have unpaired chromosomes but not from parents that are normal diploids. Blood tests established that the male foal, appropriately named Blue Moon, was the offspring of Krause and that Krause was indeed a mule. Both Blue Moon and Krause were fathered by the same donkey (see the illustration). The foal, like his mother, had 63 chromosomes-half of them horse chromosomes and the other half donkey chromosomes. Analyses of genetic markers showed that, remarkably, Blue Moon seemed to have inherited a complete set of horse chromosomes from his mother, instead of the random mixture of horse and donkey chromosomes that would be expected with normal meiosis. Thus, Blue Moon and Krause were not only mother and son, but also brother and sister. With the use of a diagram, show how, if Blue Moon inherited only horse chromosomes from his mother, Blue Moon and Krause are both mother and son as well as brother and sister. Although rare, additional cases of fertile mules giving births to offspring have been reported. In these cases, when a female mule mates with a male horse, the offspring is horselike in appearance but, when a female mule mates with a male donkey, the offspring is mulelike in appearance. Is this observation consistent with the idea that the offspring of fertile female mules inherit only a set of horse chromosomes from their mule mothers? Can you suggest a possible mechanism for how the offspring of fertile female mules might pass on a complete set of horse chromosomes to their offspring? Humans and many other complex organisms are diploid, possessing two sets of genes, one inherited from the mother and one from the father. However, a number of eukaryotic organisms spend most of their life cycles in a haploid state. Many of these eukaryotes, such as Neurospora and yeast, still undergo meiosis and sexual reproduction, but most of the cells that make up the organism are haploid. Considering that haploid organisms are fully capable of sexual reproduction and generating genetic variation, why are most complex eukaryotes diploid? In other words, what might be the evolutionary advantage of existing in a diploid state instead of a haploid state? In 1856, a group of men working a limestone quarry in the Neander Valley of Germany discovered a small cave containing a number of bones. The workers assumed that the bones were those of a cave bear, but a local schoolteacher recognized them as human, although they were clearly unlike any human bones the teacher had ever seen. The bones appeared to be those of a large person with great muscular strength, a low forehead, a large nose with broad nostrils, and massive protruding brows. Experts confirmed that the bones belonged to an extinct human, who became known as Neanderthal. In the next 100 years, similar fossils were discovered in Spain, Belgium, France, Croatia, and the Middle East. Research has now revealed that Neanderthals roamed Europe and western Asia for at least 200,000 years, disappearing abruptly 30,000 to 40,000 years ago. During the last years of this period, Neanderthals coexisted with the direct ancestors of modern humans, the Cro-Magnons. The fate of the Neanderthals-why they disappeared-has captured the imagination of scientists and laypersons alike. Did Cro-Magnons, migrating out of Africa with a superior technology, cause the demise of the Neanderthal people, either through competition or perhaps through deliberate extermination? Or did the Neanderthals interbreed with Cro-Magnons, their genes becoming assimilated into the larger gene pool of modern humans? Support for the latter hypothesis came from the discovery of fossils that appeared to be transitional between Neanderthals and Cro-Magnons. Unfortunately, the meager fossil record of Neanderthals and Cro-Magnons did not allow a definitive resolution of these questions. Comparison of the genomes of modern humans and Neanderthals reveal evidence of some interbreeding between the two groups. This information must have the capacity to vary, because different species and even individual members of a species differ in their genetic makeup. At the same time, the genetic material must be stable, because alterations to the genetic instructions (mutations) are frequently detrimental. A second necessary feature is that genetic material must have the capacity to be copied accurately. Every organism begins life as a single cell, which must undergo billions of cell divisions to produce a complex, multicellular creature like yourself. At each cell division, the genetic instructions must be transmitted to descendant cells with great accuracy. When organisms reproduce and pass genes on to their progeny, the coding instructions must be copied with fidelity. The genetic material (the genotype) must have the capacity to "code for" (determine) traits (the phenotype). The product of a gene is often a protein; so there must be a mechanism for genetic instructions to be translated into the amino acid sequence of a protein. Surprisingly, the idea that genes are made of nucleic acids was not widely accepted until after 1950. Even before nucleic acids were identified as the genetic material, biologists recognized that, whatever the nature of the genetic material, it must possess three important characteristics. Pus contains white blood cells with large nuclei; Miescher developed a method for isolating these nuclei. The minute amounts of nuclear material that he obtained were insufficient for a thorough chemical analysis, but he did establish that the nuclear material contained a novel substance that was slightly acidic and high in phosphorus.