Colospa
Jennifer Lynn Garst, MD
- Professor of Medicine
- Member of the Duke Cancer Institute
https://medicine.duke.edu/faculty/jennifer-lynn-garst-md
By comparison spasms from acid reflux order cheap colospa on-line, the term genetic screening refers to population-wide genetic testing quetiapine spasms colospa 135mg visa. Samples from individuals affected with Tay-Sachs spasms near tailbone generic colospa 135 mg online, who do not produce the HexA enzyme muscle relaxant pain reliever cheap colospa 135mg overnight delivery, produce little or no fluorescence spasms around the heart order colospa 135 mg online, whereas samples from individuals who are homozygous for the normal hexA allele produce a high level of fluorescence spasms in throat purchase 135mg colospa free shipping. Samples from heterozygotes, who have 50% HexA activity, produce intermediate levels of fluorescence. To apply this testing strategy, researchers must have previously identified the mutant gene using molecular techniques. The identification of many human genes, such as those involved in Duchenne muscular dystrophy, cystic fibrosis, and Huntington disease, has made it possible to test for affected individuals or those who may be carriers of these diseases. Many human genetic abnormalities involve changes in chromosome number and/or structure. In fact, changes in chromosome number are a common class of human genetic abnormality. Most of Genetic Testing Is Used to Identify Many Inherited Human Diseases Table 22. In many cases, single-gene mutations that affect the function of proteins can be examined at the protein level. As mentioned earlier, Tay-Sachs disease is due to a defect in the enzyme hexosaminidase A (HexA). However, approximately 1 in 200 live births are aneuploid-have an abnormal number of chromosomes (see Chapter 8, Table 8. About 5% of infant and childhood deaths are related to such genetic abnormalities. Changes in chromosome number and many changes in chromosome structure can be detected by karyotyping the chromosomes with a light microscope. For example, pregnant women older than 35 often have tests conducted to see if their fetuses are carrying chromosomal abnormalities. As discussed in Chapter 8, these tests are indicated because the rate of such defects increases with the age of the mother. Genetic screening has also been conducted on specific populations in which a genetic disease is prevalent. For example, in 1971, community-based screening for heterozygous carriers of Tay-Sachs disease was begun among specific Ashkenazi Jewish populations. With the use of this screening, over the course of one generation, the incidence of births of children with Tay-Sachs disease in these populations was reduced by 90%. For most rare genetic abnormalities, however, genetic screening is not routine practice. Rather, genetic testing is performed only when a family history reveals a strong likelihood that a couple may produce an affected child. Typically, such a couple already has an affected child or has other relatives with a genetic disease. Genetic testing and screening are medical practices with many social and ethical dimensions. For example, people must decide whether or not they want to make use of available tests, particularly when the disease in question has no cure. For example, Huntington disease typically does not affect people until their 50s and can last 20 years. People who learn they are carriers of genetic diseases such as Huntington disease can be devastated by the news. Some argue that people have a right to know about their genetic makeup; others assert that it does more harm than good. Could routine genetic testing lead to discrimination by employers or medical insurance companies In the coming years, we will gain ever-increasing awareness of our genetic makeup and the underlying causes of genetic diseases. As a society, establishing guidelines for the uses of genetic testing will be a necessary, yet very difficult, task. In amniocentesis, amniotic fluid is withdrawn, and fetal cells are collected by centrifugation. The two common ways of obtaining cellular material from a fetus for the purpose of genetic testing are amniocentesis and chorionic villus sampling. In chorionic villus sampling, a small piece of the chorion (the fetal part of the placenta) is removed, and a karyotype is prepared directly from the collected cells. Chorionic villus sampling can be performed earlier during pregnancy than amniocentesis, usually around the tenth to twelfth week, compared to the fifteenth to twentieth week for amniocentesis, and results from chorionic villus sampling are available sooner. Weighed against these advantages, however, is that this procedure may pose a slightly greater risk of causing a miscarriage. The testing is typically done to check for a specific genetic abnormality, such as the allele that causes Huntington disease. Depending on the outcome of the results, a decision can be made whether or not to transfer the embryo into the uterus of the prospective mother in hopes of implantation and the eventual birth of a baby. As with the genetic screening of adults, the testing of embryos and fetuses raises many ethical questions. This single cell and its line of daughter cells undergo a series of genetic changes that accumulate during cell division. A hallmark of a cancer cell is that it divides to produce two daughter cancer cells. Cancer cells are invasive-they can invade healthy tissues-and metastatic-they can migrate to other parts of the body and cause secondary tumors. Which of the following prenatal genetic testing methods is done in conjunction with in vitro fertilization All of the above are usually performed in conjunction with in vitro fertilization. Malignant growth Invasion of surrounding tissue and metastasis into bloodstream 22. More than 100 kinds of human cancers have been identified, and they are classified according to the type of cell that has become cancerous. Though cancer is a diverse collection of many diseases, some characteristics are common to all cancers. Genes Traits In a healthy individual, one or more gene mutations convert a normal cell into a tumor cell. Additional genetic changes in the tumor cells may occur, leading to malignant growth. At a later stage in malignancy, the tumor cells invade surrounding tissues, and some malignant cells may metastasize by traveling through the bloodstream to other parts of the body, where they can grow and cause secondary tumors. As a trait, cancer can be viewed as a series of genetic changes that eventually lead to uncontrolled cell growth. Rather, cancer is usually an acquired condition that typically occurs later in life. Although some cancers are caused by spontaneous mutations and viruses, at least 80% of all human cancers are related to exposure to agents that promote genetic changes in somatic cells. The effects of these mutations are placed into two broad categories: An oncogene is a mutant gene that is overexpressed and contributes to cancerous growth. A loss-of-function mutation in a tumor-suppressor gene can allow cancerous growth to occur. Therefore, oncogenes and tumor suppressor genes are distinguished by whether a cancer-causing mutation increases or decreases gene expression. These epigenetic changes can promote cancer by increasing the expression of oncogenes or inhibiting the expression of tumor-suppressor genes. As noted in the preceding section, an oncogene is a mutant gene that is overexpressed and contributes to the development of cancer. A normal, nonmutated gene that has the potential to become an oncogene is termed a proto-oncogene. To become an oncogene, a proto-oncogene must incur a mutation that causes its expression to be abnormally high. Such a mutation is another example of a gainof-function mutation, which we discussed earlier in this chapter in the context of dominant mutations. A gain-of-function mutation that produces an oncogene typically has one of three possible effects: the amount of the encoded protein is greatly increased. A change occurs in the structure of the encoded protein that causes it to be overly active. The encoded protein is expressed in a cell type where it is not normally expressed. In this section, we will explore the possible ways that oncogenes affect cell growth and examine the types of genetic changes that convert proto-oncogenes into oncogenes. Depending on the conditions, a cell in the G1 phase may accumulate molecular changes that cause it to advance through the rest of the cell cycle. When this occurs, cell biologists say that a cell has reached a special control point called the restriction point. For example, environmental conditions, such as the presence of sufficient nutrients, are important for cell division. In addition, multicellular organisms rely on signaling molecules to coordinate cell division throughout the body. These signaling molecules are often called growth factors because they promote cell division. As researchers began to investigate cancer at the molecular level, they wanted to understand how mutant genes promote abnormal cell division. In parallel with cancer research, cell biologists have studied the roles that normal cellular proteins play in cell division. As mentioned, the cell cycle is regulated in part by growth factors that bind to cell surface receptors and initiate a cascade of cellular events that lead eventually to cell division. Cancer can be caused by mutations that overexpress oncogenes or that inhibit the expression of tumor-suppressor genes. This activation leads to the transcription of genes, which encode proteins that promote cell division. This pathway, also known as a signal cascade, leads to a change in gene transcription. In other words, the transcription of specific genes is activated in response to the growth factor. Once these genes are transcribed and translated, the gene products function to promote the progression through the cell cycle. Eukaryotic species produce many different growth factors, and the signaling pathways are often more complex than the one shown here. The mutations that convert proto-oncogenes into oncogenes have been analyzed in many types of cancers. Oncogenes commonly encode proteins that function in cell signaling pathways related to cell division (Table 22. These proteins include growth factors, growth factor receptors, intracellular signaling proteins, and transcription factors. As an example, mutations that alter the amino acid sequence of the Ras protein have been shown to cause functional abnormalities. Certain mutations that convert the normal ras gene into an oncogene decrease the ability of the Ras protein to 22. Most of the genes have been given three-letter names that are abbreviations for the type of cancer the oncogene causes or the type of virus in which the gene was first identified. Robert Gallo and Mark Groudine discovered that a gene called c-myc was amplified in a human leukemia cell line. In such cases, the extent of oncogene amplification may be correlated with the progression of tumors to increasing malignancy. These include the amplification of N-myc in neuroblastomas and erbB-2 in breast carcinomas. Chromosomal Translocation A third type of genetic alteration that can lead to cancer is a chromosomal translocation. Abnormalities in chromosome structure are common in cancer cells, and very specific types of chromosomal translocations have been identified in certain types of tumors. Rather than being due to a deletion, this shortened chromosome is the result of a reciprocal translocation between chromosomes 9 and 22. Following the reciprocal translocation, the coding sequence of the abl gene fuses with the promoter and coding sequence of the bcr gene. In this way, such mutations keep the signaling pathway turned on, thereby stimulating the cell to divide. Genetic Changes in Proto-Oncogenes Convert Them to Oncogenes How do specific genetic alterations convert proto-oncogenes into oncogenes By isolating and studying oncogenes at the molecular level, researchers have discovered four main ways this occurs. Missense Mutation As mentioned previously, changes in the structure of the Ras protein can cause it to become permanently activated. The human genome contains four different but evolutionarily related ras genes: rasH, rasN, rasK-4a, and rasK-4b.
Multisensory integration by association cortex is perturbed when sensory experience is limited during development (Carriere et al muscle relaxant 1 purchase cheap colospa on line. Similarly spasms in 6 month old baby 135mg colospa free shipping, humans deprived of audition or vision during early life display a reduced ability to integrate auditory speech cues with visual lip-reading cues (Schorr et al spasms proven 135mg colospa. The prolonged maturation of auditory and visual skills spasms during sleep purchase colospa 135 mg free shipping, discussed above muscle relaxant lyrics generic colospa 135 mg amex, may be linked to protracted developmental changes found in the human brain stomach spasms 6 weeks pregnant cheap 135mg colospa visa. On one side of the device, the cloth is placed immediately beneath the plexiglass, and on the other side it is placed 4 ft below. The majority of infants would not crawl onto the seemingly unsupported surface, even when their mothers beckoned them from the other side. Despite the early appearance of face recognition, the ability to discriminate between faces does not reach maturity for almost 2 decades. The auditory (green), somatosensory (red), and visual (blue) receptive fields are shown for example neurons recorded from cats at three different ages. The relative size of visual, auditory, and somatosensory receptive fields are plotted for neurons recorded throughout development (right). Although the 8-week neuron fires to both somatosensory (red) and auditory (green) stimulation, its firing rate shows no facilitation when both sensory modalities are stimulated together (yellow). In contrast, the 20-week neuron does display facilitation when visual and auditory stimuli are presented together. Perhaps the longest developmental trajectory occurs for axonal myelination which continues to mature until about 30 years in humans, and has a similar timecourse in nonhuman primates (Lebel and Beaulieu, 2011; Yeatman et al. A challenge for future research will be to demonstrate a causal link between these neural changes and behavior. While the debate is seductive, the relationship between brain development and sexual behavior varies tremendously from species to species. Since mating and maternity have been most thoroughly explored at the neural level, we will mostly focus on these behaviors. However, it is worth mentioning some complex behaviors that differ between male and female animals. Predatory behavior is sexually dimorphic in lions (females do more of it), urination posture is sexually dimorphic in dogs (males elevate one leg), and olfactory signaling is sexually dimorphic in moths (females produce a pheromone). In both rats and monkeys, young animals engage in play behavior that differs between the sexes, at least in its frequency of occurrence. These fights will typically begin with one animal jumping onto the other, and they end with one animal on top of the other. When testosterone is given to a pregnant monkey, the play behavior of her female offspring becomes more male-like (Abbott and Hearn, 1978). Evidence of sexually distinct behavior in humans has emerged from the prevalence of certain neurological and psychiatric diseases in males vs females. For example, both dyslexia and schizophrenia are more prevalent in males (about 75% of cases), while anorexia nervosa is more prevalent in females (over 90% of cases). Many studies have also focused on the cognitive abilities of normal adult humans (Kimura, 1996). A gradual increase in neurofilament-positive fibers is observed during the first 10 years of life. There is a gradual increase in 1 expression and a reduction in 2 expression over the first 10 years. In contrast, when presented with a picture containing many objects, females are better able to say which objects have been moved in a second picture. While these results tend to fascinate us, the challenge will be to understand their relevance to natural behavior and the underlying neural mechanisms. Certain sexual characteristics emerge during embryonic development, such as differentiation of the genitals and the motor neurons that innervate them (see Chapter 7). The nervous system continues to respond to steroid hormones throughout life, making it important to ask whether a dimorphism is induced by early exposure to a hormone, or whether it can be elicited during adulthood, in either sex, merely by adjusting the amount of a circulating hormone. For example, even before puberty, one region of the amygdala has a greater volume and 80% more excitatory synapses in male rats than in females, indicating that the dimorphism is induced developmentally. Castration of adult males causes the volume to shrink to female values, and androgen treatment of adult females enlarges the structure to the average male size (Cooke et al. Therefore, we will begin by examining the early determinants of gender and then explore determinants of behavior and brain development. After primary sex determination is complete, all sex differences, including those of the nervous system, were originally thought to originate from the gonads. However, the genetic sex of somatic cells may play a role in their differentiation, and genomic imprinting biases brain development toward one of the parents. The principal importance of gonadal hormones is powerfully demonstrated by removing the gonads before primary determination occurs (Jost, 1953). Furthermore, their sexual behavior is female-like, presumably because certain areas of the nervous system have developed female characteristics (Phoenix et al. Testosterone levels rise during the perinatal period, decrease after birth, and rise again at puberty. That is, they do not arch their back (lordosis) when approached by a male, and will mount a female rat if given a dose of testosterone. Interestingly, most of these individuals who were raised as girls, nonetheless chose to adopt a male identity during or after puberty. In fruit flies and other insects, the genetic sex of each cell is the key determinant. If it has two Xs, then the cell expresses a protein called sexlethal and becomes female. The nematode, Caenorhabditis elegans, also comes in two categories, but they are male and hermaphrodite. The genetic sex of each cell in a mammal is specified by the presence of either two X chromosomes (female) or one X and one Y (male). However, the genetic sex of most somatic cells is not thought to have an immediate influence on their development. Primary sex determination refers to differentiation of the gonadal tissue, and this is determined by the Sry gene on the Y chromosome, which encodes a transcription factor (Goodfellow and Lovell-Badge, 1993; Sekido and Lovell-Badge, 2009). Androgen receptors are expressed at highest concentration in the hypothalamus and limbic structures. Estradiol receptors are found in neurons of the hypothalamus and amygdala, and they are expressed transiently in the cortex and hypothalamus. At first, this might seem puzzling because estradiol is secreted by the ovaries and promotes differentiation of the female reproductive organs. However, testosterone is also an intermediate metabolite of estradiol in the ovaries. In primates, androgen appears to be the main source of brain masculinization (Swartz and Soloff, 1974; Wallen, 2005). In contrast, genetic males with an aromatase dysfunction display normal male behavior (Grumbach and Auchus, 1999). There are at least two factors that allow estradiol to act selectively on the brains of genetic males. First, aromatase activity is higher in the brains of male mice, particularly during the prenatal and neonatal periods (Hutchison, 1997). Second, the blood of young animals contains an estradiolbinding protein, called -fetoprotein, which may prevent estrogen secreted by the ovaries from reaching the brain (Uriel et al. When the -fetoprotein gene was deleted, genetic females displayed masculine sexual behavior and neurochemical characteristics. However, the female phenotype was rescued by preventing the conversion of testosterone to estradiol (Bakker et al. For example, medial preoptic neurons fire rapidly just prior to male copulation, and copulatory behavior is disrupted when this area is lesioned. Medial preoptic neurons are also known to take up more testosterone than any other brain region in adult animals. One of the first studies to demonstrate secondary sex determination in the nervous system was an ultrastructural analysis of the preoptic area (Raisman and Field, 1973). Similar dimorphisms are found in the primate hypothalamus, including that of humans. However, the number of neurons declines more rapidly during development in females (Swaab and Hofman, 1988). Furthermore, this nucleus can be enlarged in genetic females when they are treated with testosterone as neonates (Gorski et al. Estradiol causes the upregulation of prostaglandin-E(2), and administration of this signal can masculinize the nucleus and lead to adult male copulatory behavior (Amateau and McCarthy, 2004). Estradiol and testosterone have a dramatic effect on both neurite outgrowth and dendritic branching in organotypic cultures of the mouse hypothalamus (ToranAllerand, 1980; Toran-Allerand et al. Photomicrographs (left) show labeled spines, indicating large (L) and giant (G) spine heads. The bar graph (right) illustrates the magnitude of the difference between males and females. A sagittal section through the brain of song birds shows major nuclei involved in the learning and production of vocalizations. In rats, females display a greater density of dendritic spines, particularly those with very large spine heads, suggesting that excitatory drive might be greater (Forlano and Woolley, 2010). Male birds attract a mate of the same species with vocalizations, or songs, that are learned during juvenile development or adulthood. Zebra finches learn one song after hatching, while canaries add new phrases to their song each breeding season. When scientists first looked at the brains of these animals, they were startled to find regions of remarkably dif- ferent size in each sex (Nottebohm and Arnold, 1976). Furthermore, when hatchling females are treated with estradiol, they can grow up to sing almost as adeptly as genetic males (Gurney and Konishi, 1980; Simpson and Vicario, 1991). In male canaries, the size of vocal control nuclei changes during the course of a single breeding season, getting larger as testosterone levels rise (Nottebohm, 1981). Hormone treatment can enhance the size of brain nuclei, both by increasing afferent innervation and promoting dendritic growth. Although most female songbirds tend not to vocalize during mating, female tropical wrens do sing a "duet" with the males. In fact, when the song repertoire of a female wren Behavioral Development Chapter 10 339 becomes relatively large, its song-control nuclei reach a size similar to that of males (Brenowitz and Arnold, 1986). The male Xenopus mating call has been well-characterized and, like birds, there is a sexual dimorphism of both neural and muscular components that support song production (Kelley, 1997). However, female vocal behavior, termed rapping, is thought to trigger the entire copulatory repertoire (Tobias et al. When the female frog is unreceptive, it produces a ticking sound, but when it is ready to lay eggs, it begins to rap. This call stimulates males to vocalize even more vigorously and to attempt copulation. In Xenopus, both sexes have the same central networks for vocalization behavior, and circulating testosterone is necessary for the male-specific vocalizations (Yu and Yamaguchi, 2009). Sex-specific differentiation has been observed at the level of vocal motor neuron membrane properties, and this may lead to different output patterns for males and females (Yamaguchi et al. Male fruit flies recognize females based on an olfactory cue, called a contact pheromone, and males perform a stereotyped courtship behavior when they detect this signal. The male orients towards a female, taps her abdomen, flutters his wings in song, and places his proboscis (the mouthparts) on the genitals. How does the central nervous system create this complex set of sexspecific behaviors By studying many flies of this sort, each with a unique mosaic, it is possible to determine which brain cells must be male or female such that the proper behavior is displayed (Hall, 1977). Whenever the enhancer is activated by a transcription factor, a reporter gene within the enhancer trap is expressed. The enhancer trap line can also be used to drive the expression of native genes, such as transformer (green). An enhancer trap system has been used to express a feminizing signal (transformer) in olfactory neurons that process the contact pheromone (Ferveur et al. Genetic males that express transformer were presented with flies of either sex to see whether they selectively court the female, as normal males do. The behavior of transformed animals may be due to their failure in discriminating the female pheromone. When the enhancer trap technique was used to make male flies that secrete only female pheromones, these flies were courted as if they were females (Ferveur et al. Thus, 340 Development of the Nervous System in flies, specific brain regions must have a gender if animals are to accurately interpret sensory information and produce sexually appropriate motor responses. A separate tack has been used to explore the genes which must be expressed in male or female nerve cells in order to produce correct sexual behaviors (Hall, 1994; Manoli et al. For example, a sex-specific splice-form of the transcription factor, fruitless, is expressed in about 500 neurons of male flies only, and mutations of this gene also cause males to court one another. A mutation of the dissatisfaction gene leads virgin females to resist males during courtship, and they fail to lay mature eggs (Finley et al. Most mutations that affect sexual activity in flies are also found to affect other behaviors. Mutations of the period gene affects circadian rhythms, but they also change the temporal properties of the courtship song.
Give an example of an inhaled anesthetic with a low blood/gas partition coefficient (low blood solubility): Give an example of an inhaled anesthetic with a high blood/gas partition coefficient (high blood solubility): Which inhaled anesthetic spasms right side of back purchase colospa 135 mg, halothane or nitrous oxide muscle relaxant used for migraines order colospa in india, will take longer to change the depth of anesthesia when the concentration of the inhaled anesthetic has been changed Are the inhaled halogenated hydrocarbon anesthetics volatile or nonvolatile gases Should a patient with a family history positive for malignant hyperthermia be concerned Which inhaled anesthetics increase heart rate (via reflex secondary to vasodilation) Increase Increase Relax (except methoxyflurane when briefly inhaled muscle relaxant soma discount colospa amex, therefore spasms verb buy 135 mg colospa visa, can be used during childbirth) Nitrous oxide Volatile gases All halogenated hydrocarbons and depolarizing muscle relaxants (succinylcholine) Hypercarbia spasms under rib cage generic colospa 135mg with visa, tachycardia muscle relaxant ibuprofen discount 135 mg colospa with mastercard, hyperthermia; muscle rigidity; acidosis; hypertension; hyperkalemia Yes, because a genetic defect in ryanodine receptors may be inherited Dantrolene Blocks the uncontrolled release of calcium from the sarcoplasmic reticulum in skeletal muscle Halothane Pediatric patients Nitrous oxide Halothane Isoflurane; desflurane 74 Zoom Review: Pharmacology Which inhaled anesthetic decreases renal and hepatic blood flow State whether thiopental increases, decreases, or does not change each of the following physiologic effects: Cerebral blood flow Respiratory function Blood pressure Why should caution be taken when administering thiopental to asthmatic patients Midazolam offers which type of amnesia making it useful for monitored anesthesia care Ketamine Increase Propofol Weak bases In an acidic environment, local anesthetics become ionized and are unable to diffuse across membranes, leading to accumulation of the drug and possible toxicity Lidocaine; prilocaine; articaine; mepivacaine; bupivacaine (all have >1 "i" in their generic name) Cocaine; benzocaine; procaine (all have only one "i" in their generic name) Epinephrine, by inducing a local vasoconstriction Give examples of amide local anesthetics: Give examples of ester local anesthetics: Which medication, when used in combination, reduces systemic toxicity and increases the duration of action of local anesthetics Epinephrine should not be combined with local anesthetics when injecting near which anatomic sites Which type of enzymes metabolize amide local anesthetics and where are they located Digits; nose; ears; penis; and any endartery circulation Amidases located in the liver 76 Zoom Review: Pharmacology Which type of enzymes metabolize ester local anesthetics and where are they located Esterases located in tissues and blood Inhibition of sodium channels in axonal membranes via binding to the channels in their inactivated state and preventing a structural change to the resting state Ionized form Do local anesthetics need to be in the ionized or nonionized form to bind to the sodium channel Do local anesthetics need to be in the ionized or nonionized form to gain access to the sodium channel, which is located on the inner side of the axonal membrane What is the mechanism of action of medications that activate presynaptic opioid receptors What is the mechanism of action of medications that activate postsynaptic opioid receptors Meperidine (antagonizes muscarinic receptors) 78 Zoom Review: Pharmacology Do opioid analgesics increase or decrease uterine contractions during pregnancy They decrease uterine contractions; thus, a good contraction pattern should be achieved before placement of an epidural catheter during labor Miosis (common sign of opioid overdose is pinpoint pupils) Increased parasympathetic (cholinergic) activity in the pupillary constrictor muscles Meperidine (antagonizes muscarinic receptors) 1. Dextromethorphan Opioids suppress the cough reflex What is the mechanism of opioidinduced urinary retention What adverse effect (other than respiratory depression) may be seen when opioids are administered quickly in large doses Which opioid analgesic is used to prevent withdrawal symptoms in patients discontinuing heroin use Which central-acting 2-agonist is used to prevent withdrawal symptoms in patients discontinuing heroin use Give examples of strong opioid agonists: Give examples of weak opioid agonists: Give examples of partial opioid agonists: Propoxyphene is a derivative of which opioid analgesic Dextromethorphan these combinations may produce serotonin syndrome Heroin (is converted back to morphine in vivo) No (must be metabolized via cytochrome P-450 2D6 to active morphine) Acetaminophen What drug do you get by acetylating morphine Which medication is commonly given in combination with codeine for the treatment of pain Which metabolite of ethanol is responsible for causing headache, hypotension, nausea, and vomiting ("hangover") Give examples of benzodiazepines: Duration Increased chloride ion influx into cells, leading to membrane hyperpolarization and subsequent decreased neuronal firing Increased potassium ion efflux out of cells, leading to membrane hyperpolarization and subsequent decreased neuronal firing Baclofen Muscle relaxation 1. Temazepam these medications can be administered to a patient with liver failure (lorazepam treats delirium tremens in an alcoholic who might have liver failure) Which benzodiazepines are commonly used as anticonvulsants Why is alprazolam not the drug of choice when treating patients with chronic anxiety Short-acting benzodiazepines (abrupt withdrawal may ensue as drug levels are rapidly decreased vs. Seizures (generalized tonic-clonic and partial seizures) Induction of anesthesia; no longer available in the United States Sedation; hypnosis Induction of cytochrome P-450 enzymes Drowsiness; impair cognitive function (especially in pediatric patients); "hangover" effect; nausea; dizziness; increase heme synthesis (contraindicated in patients with acute intermittent porphyria); coma; respiratory depression; cardiovascular depression; addiction 84 Zoom Review: Pharmacology Give examples of barbiturate withdrawal signs and symptoms: What drug class is used to prevent barbiturate withdrawal Name an 2-antagonist that is used in the treatment of erectile dysfunction: What is the mechanism of action of venlafaxine When is lithium used in the treatment of manic-depression (what phases of the disease) What is the name of the cardiac anomaly that may be found in neonates born to mothers using lithium and what characterizes this anomaly What other medications (mood stabilizers) may be used in the treatment of manic-depression Why are antidepressant agents not used to treat the depression phase of manic-depression Characterize the antimuscarinic activity of chlorpromazine and thioridazine: Which antipsychotic agents are more effective at treating negative symptoms Which phenothiazine antipsychotic may cause priapism, agranulocytosis, blue-gray discoloration of the skin, and lower seizure threshold Which two typical antipsychotics can be formulated as depot intramuscular injections that may last up to 3 weeks Which atypical antipsychotic is usually reserved as a third-line agent to treat schizophrenic patients refractory to traditional therapy Methamphetamine Cardiovascular stimulation (hypertension, tachycardia, palpitations; arrhythmias; angina) 1. What medication provides modest survival benefit to patients with amyotrophic lateral sclerosis Myoclonic Hyperventilation (via alkalinization of blood pH) Tonic-clonic seizure Tonic-clonic seizure Absence seizure 96 Zoom Review: Pharmacology What is status epilepticus Epileptic seizure lasting longer than 30 minutes or absence of full recovery of consciousness between seizures (can be life threatening) Inhibit initiation of an abnormal electrical discharge from the focal area; prevent dissemination of abnormal electrical discharge to surrounding areas of the brain Inhibition of axonal sodium channels to produce membrane stabilization; also provides phenytoin with antiarrhythmic activity Inactivated state In general, how do antiepileptic agents work Does phenytoin inhibit the axonal sodium channel in its activated or inactivated state What prodrug is hydrolyzed to phenytoin and is commonly given intravenously secondary to its superior water solubility versus phenytoin Name two other medications that may cause gingival hyperplasia: Which types of seizures does phenytoin treat Which antiepileptic medication is used to treat partial and tonic-clonic seizures during pregnancy Diazepam; lorazepam Clonazepam Ethosuximide Inhibition of T-type calcium channels in the thalamus 98 Zoom Review: Pharmacology What are the adverse effects of ethosuximide Give examples of medications in the "triptan" drug class: What is the mechanism of action of sumatriptan How long after the first dose can a second dose of sumatriptan be given if migraine headache has not resolved To avoid repeating the same therapy he does not reveal that he was previously treated for his major depressive disorder. He develops a generalized tonic-clonic seizure shortly after admission to the emergency room. Treatment of serotonin syndrome is largely supportive, but cyproheptadine may be used. Bilateral auscultation confirms equal breath sounds, and stat chest x-ray reveals no pneumothorax. What intravenous anesthetic agent is most likely responsible for this development Fentanyl, a synthetic high-potency opioid, is frequently used as a part of balanced anesthesia and can cause chest wall and laryngeal rigidity, interfering with mechanical ventilation. As it has a hemodynamically favorable profile, it may be used in larger doses during induction to avoid hypotension, and an emergency surgery would require rapid induction and bolus of medication. Chest wall rigidity is most commonly seen with rapid, large-dose opioid administration. Treatment is administration of a longer acting depolarizing muscle relaxant and continued mechanical ventilation. What is the most likely therapy she is receiving for her disease, and why might the medication be responsible for her current situation What fast-acting dopamine agonist would be appropriate for use in such a situation Patients may find they are suddenly unable to stand or walk and may require rescue therapy with a fast-acting dopamine agonist. Apomorphine is such an agent, and is useful in acute situations such as that presented in the vignette. It does not require enzymatic conversion to an active product, and so works quickly-about 10 minutes after injection. Nausea and vomiting limit its use to rescue situations, as does dyskinesia and hypotension. His mother reports that he was very agitated and confused after his last surgery, and wonders if there is any way to avoid this occurrence again. A short-acting benzodiazepine, midazolam is frequently given preoperatively to both children and adults. Since benzodiazepines can cause memory loss, disorientation and delirium are common, particularly in children and the elderly. As this patient had a known adverse response, discussion with the mother and consideration of alternate treatment options may be reasonable. Acutely, she develops muscular contractions with rigidity so severe she is unable to turn her head. Extrapyramidal symptoms are treated with anticholinergic/antihistaminic medications. What supplement, important in all pregnant women, should this patient be started on prior to conception Seizure control during pregnancy is important, as even seizures which do not result in maternal hypoxia can have negative effects on the fetus. Seizures may be more frequent in the third trimester because of sleep deprivation, hyperventilation, pain, and stress. There exists a small but increased risk of birth defects with several antiepileptics such as neural tube defects already mentioned with valproate and carbamazepine, digital hypoplasia with phenytoin, and cleft palate with the barbiturates. Levetiracetam and lamotrigine are frequently used in epileptic patients of child-bearing age. On what phase(s) of the cardiac action potential do lidocaine, flecainide, and quinidine work What is responsible for maintaining the electrochemical gradient at resting membrane potential H (inactivating) the cells are already partly depolarized at rest -Blockers What are the three states the voltage+ gated Na channel exists in Encainide; flecainide; propafenone; moricizine Propranolol; esmolol; metoprolol Amiodarone; sotalol; ibutilide; dofetilide Verapamil; diltiazem 1. Propafenone, even though a class Ic antiarrhythmic, exhibits what other type of antiarrhythmic activity Because the atrium is not contracting as whole unit in atrial fibrillation, the atrial kick is lost; ventricular filling decreases; high heart rates decrease the time in diastole, the time for ventricular filling; poor ventricular filling will decrease cardiac output Lidocaine; phenytoin Digoxin-induced arrhythmias are treated by what drugs What type of angina is caused by atherosclerosis of coronary vessels and is precipitated by exertion Why must patients have at least a 10- to 12-hour "nitrate-free" interval every day Methemoglobin formation, specifically by amyl nitrite, can be used to treat what type of poisoning What transporter (in the distal convoluted tubule) is inhibited by thiazide diuretics Give examples of thiazide diuretics: Thiazide diuretics may be ineffective in patients with creatinine clearances of less than what With regard to blood concentrations, state whether each of the following electrolytes will be increased or decreased in patients on thiazide diuretic therapy: Calcium Magnesium Potassium Sodium With regard to increased renal calcium reabsorption, what are thiazide diuretics sometimes used for Give examples of loop diuretics: Which loop diuretic can be given safely to patients with allergy to sulfonamide antimicrobials What transporter (in the thick ascending loop of Henle) is inhibited by loop diuretics Which renal tubular segment is responsible for the majority of sodium reabsorption Dorzolamide Increased excretion of sodium and bicarbonate Metabolic acidosis Altitude sickness (decreases cerebral and pulmonary edema); glaucoma (decreases aqueous humor formation thereby decreasing intraocular pressure); metabolic alkalosis; to enhance renal excretion of acidic drugs. Mannitol used in large doses or in patients with kidney failure can lead to what adverse effects Name three potassium-sparing diuretics: Cardiovascular/Renal Agents 119 What is the mechanism of action of spironolactone
When these axons are treated with cytochalasin spasms left side under rib cage purchase generic colospa on-line, the axons fail to make the appropriate posterior turn quinine muscle relaxant buy 135 mg colospa, and most axons miss the tectum (bottom) muscle relaxant jaw pain buy discount colospa 135 mg online. Microtubules are the other main cytoskeletal elements of the growth cone (Kahn and Baas spasms synonyms buy cheap colospa 135 mg line, 2016) spasms going to sleep trusted colospa 135 mg. Pools of unassembled tubulin are concentrated in the growth cone spasms hindi meaning colospa 135 mg for sale, which is the most sensitive part of the axon to the effects of microtubule depolymerizing agents such as nocodozole (Brown et al. Natural microtubule stabilizing proteins, such as Tau, are also highly concentrated near the growth cone, suggesting that this is where unpolymerized tubulin is fashioned into microtubules and stabilized. Like the actin filaments in the filopodia, the microtubules of the axons have a "plus" end where polymerization takes place, and this is positioned towards the growing tip. Depolymerization of microtubules inhibits axon elongation completely, showing that unlike actin assembly, microtubule growth is absolutely essential for this process (Marsh and Letourneau, 1984). Inside of the growth cone, carboxyl terminal tyrosine is added to alpha-tubulin by the enzyme tubulin tyrosine ligase. This tyrosinated form of tubulin is sensitive to depolymerizing agents so the new microtubules within the growth cone are very dynamic. In contrast, microtubules in which tubulin loses the tyrosine and becomes acetylated instead, as it does in the axon shaft, become stabilized (Brown et al. This instability of nonacetylated microtubules is critical for normal growth cone motility. A reagent like taxol which stabilizes microtubules, when applied to growth cones, causes them to advance relentlessly straight ahead, and inhibits turning (Williamson et al. This is demonstrated in experiments where the microtubule stabilizing agent taxol was delivered just on one side of a growth cone. The growth cone turns in that direction, while if a depolymerizing agent such as nocodazole is delivered to one side, the growth cone turns the other way (Buck and Zheng, 2002). The similarity of the results with actin and microtubule destabilizers suggests that actin bundles and microtubules interact in ways that are critical for proper growth cone navigation. The keys to making the growth cone cytoskeleton so dynamic are the numerous proteins that interact with actin filaments and microtubules. Chief among these are motor proteins, such as myosin that drives retrograde flow of actin (Schaefer et al. Wiring Up the Brain: Axon Navigation Chapter 5 131 but this effect is rescued if myosin activity is also inhibited (Kahn and Baas, 2016). The other key microtubule-based motors are the kinesins that take cargo toward the growing plus-ends of microtubules. There are a large number of receptors on the growth cone surface that sense the substrates and guidance molecules that the growth cone encounters in its journey and when activated, these receptors set in motion signaling cascades (see below) that regulate the activity of all these cytoskeletal proteins as the growth cone navigates. In dynein compromised growth cones, fewer microtubules enter the peripheral domain, Growth cones navigate through biological terrain that is mechanically heterogeneous. There are obvious mechanical features of the environment that affect growth cone navigation, such as nerve sheathes and the outer surfaces of the brain, which form impenetrable barriers and the presence of major pathways such as tracts or commissures, which serve as bridges or major roadways from one region to another. Numerous filopodia and lamellipodia are extended and retracted quickly at the surface of the growth cone. A particular mechanical feature of the nervous system to which growth cones attend is stiffness. The stiffness of tissues can be measured by atomic force microscopy (Franze, 2011, 2013; Franze et al. Brain tissue has barely any collagen so it is extremely soft-about the consistency of cream cheese. Muscle is an order of magnitude stiffer, and bone a further two orders of magnitude stiffer. It can be shown by plating cells into culture on substrates that differ only in stiffness that this this mechanical feature has dramatic effects on growth cones and axon growth. Much of the work on growth cone cell biology has been done in tissue culture, where the plastic petri dishes on which the neurons grow are as hard as bone. Yet when grown on substrates as soft as brain, different neurons respond differently-spinal axons branch more while sensory neurons of dorsal root ganglia grow shorter axons. On such stiff substrates the axons of retinal ganglion cells tend to grow straight and often fasciculate with each other. When grown instead on substrates that are as soft as brain tissue, these axons grow in a more exploratory mode, changing directions frequently (Koser et al. When grown on gradients of stiffness that mimic those in the brain, retinal growth cones tend to turn toward softer and away from harder, and this matches the way that they grow along gradients of stiffness in the embryonic brain. When these channels are blocked by mutation or a particular component of spider venom, growth cones lose the ability to respond to tissue stiffness (Koser et al. Mechanical support is necessary and its heterogeneity is influential, but for axons to grow to very specific target cells, molecular mechanisms are needed, and indeed, most investigations of axon guidance have focused on the molecules that support and guide navigating axons. A simple demonstration of the importance of molecular adhesion is that neurons plated on plain glass or tissue culture plastic, rarely put out axons with active growth cones, but when these same substrates are coated with a polycationic substrate, such as polylysine, that sticks well to negatively charged biological membranes, the neurons are much more likely to initiate axonal outgrowth. The growth cones of such neurons flatten against the substrate adhering very strongly to it and will follow adhesive versus nonadhesive tracks on the culture dish (Letourneau, 1975; Hammarback et al. Axons may use gradients of relative adhesiveness to orient during parts of their journey. For instance, in the moth, sensory neurons at the wing tip send out axons that grow proximally toward the base of the wing (Nardi and Vernon, 1990). Microscopic examination of the epithelium along which these axons grow show that it becomes increasingly loaded with adhesion molecules toward the base. Transplantation experiments confirm that these axons respond to this gradient as they readily cross onto a more adhesive transplant that has been moved in the proximal to distal direction, but avoid less adhesive distal transplants that have been moved proximally (Nardi, 1983). On a less adhesive substrate, growth cones are more compact, rounded, have fewer processes, and often move more quickly. Integrins are composed of various alpha and beta subunits that bind to a variety of different extracellular matrix components with distinct affinity profiles. Neurite growth rate can then be measured on these same substrates for comparison (Lemmon et al. For an axon to grow quickly, the substrate must have the right amount of stickiness-too little and the growth cone will not attach, too much and the growth cone will get stuck. Indeed, the most adhesive substrates, such as the lectin Concanavalin A, do not support axon outgrowth; growth cones on such a surface are exceedingly flattened and seem incapable of even retracting their filopodia. Laminin, Fibronectin, Vitronectin, and various forms of collagen, all promote axon outgrowth. The alpha5 subunit is particularly good at binding to Fibronectin, while the alpha6 subunit is better at binding to Laminin. For instance, chick retinal ganglion cells axons express alpha6 and grow well on Laminin when they are growing along the first legs of their journey in the retina and the optic tract. Thus, the response of an axon to particular extracellular matrix molecules is largely a matter of which combination of alpha and beta Integrin subunits the growth cone is expressing at the time (McKerracher et al. For example, developing motor neurons of the chick grow out of the spinal cord and enter a complicated plexus region, where they criss-cross each other in many directions until they eventually segregate into distinct nerve roots leading to their appropriate muscles. This keeps the axons that are headed toward different muscles from fasciculating with each another. If the sialic acid is digested away with endoneuraminidase, errors in pathfinding occur in the plexus region, and motor axons exit into the wrong peripheral nerves (Tang et al. Strong evidence for this hypothesis comes from studies of the embryonic grasshopper central nervous system. Here, for example, the axon of the G-neuron extends across the posterior commissure along a pathway pioneered by the Q-neurons (Bastiani et al. Once it has crossed the midline, the growth cone of the G-neuron pauses for a few hours. During this time, its filopodia seem to explore a number of different longitudinal fascicles in the near vicinity. In the electron microscope, it can be seen that filopodia from the G-neuron growth cone preferentially stick to the P-axons. The G-growth cone then fasciculates with the P-axons, which it then joins and follows anteriorly to the brain. Strikingly, if the P-axons are ablated before the G-growth cone crosses the midline, the G-growth cone upon reaching the other side does not show a high affinity for any other longitudinal bundle. In vertebrates, too, there is evidence that some axons use a labeled pathway mechanism. Just as you may have to change roads at an intersection to reach your final destination, so axons also have to change pathways. Cdhs are physiologically distinguished by the fact that they have calcium-binding domains that make them calcium sensitive. The homophilic N-Cdh is expressed throughout the nervous system and is important for the growth of axons along glial cells (Takeichi, 2007). Three gene clusters within a single chromosomal domain, each of which has several splicoforms provide enormous cell surface diversity when assembled into multimers (Chen and Maniatis, 2013; Hayashi and Takeichi, 2015). These protocadherins are remarkably homophilic, this means that cells expressing certain combinations of protocadherins can specifically recognize and adhere to each other. There are also unconventional cadherins that mediate repulsive rather than adhesive interactions such as T-cadherin, which, through a homophilic interaction, prevents motor neurons from entering the caudal halves of scleratomes on their way to their target muscles (Fredette et al. Growing axons respond to a variety of cues as they navigate, so the loss of just one of these may affect axon growth and navigation in a limited way. These findings suggest that there may be molecular redundancy for pathfinding in the developing nervous system. In support of this idea is the finding that sometimes doubly mutant embryos, which have deletions of more than one particular adhesion molecule, exhibit severe axonal growth defects, whereas each of the single mutants is relatively normal. To test whether FasI is part of a redundant system, several other mutants with putative guidance or growth cone function, each of which had no striking phenotype on its own, were crossed into a fasI mutant background. One of the double mutants tested showed pathfinding defects in combination with fasI. That both FasI and Abl had to be knocked out to cause axon disorientation suggests that these two proteins are involved in two distinct molecular pathways, either of which may suffice for axon guidance. Similarly, in vertebrate tissue culture, motor axon growth over muscle fibers is not seriously impaired unless two or more adhesion molecules are simultaneously disabled (Tomaselli et al. Axonal growth is such an important part of building an organism that such failsafe molecular mechanisms often operate to help ensure that the nervous system is properly wired. Observations of mixtures of different tissues in culture first indicated that neural tissues can produce substances that repel axons. In these sorts of experiments, the trajectories of axons are observed when they are cultured in the presence of tissues that they normally avoid. Similar results are obtained by coculturing pieces of olfactory bulb with the septum, a medial structure of the forebrain. Axons from the bulb run laterally in the forebrain appearing to grow away from the septum. When two explants are cocultured, there is usually an intermingling of axons, but in the case of retinal and sympathetic cocultures, it is apparent that the axons avoid one another. Time-lapse video films made of growth cones from one explant as they approach the axons of the other show that these growth cones collapse when they make contact with the foreign axon. Many surrounding tissues, including the epidermis, the dermomyotome, the floorplate, and the notochord, secrete diffusible repellents. A time-lapse series of a growth cone from a retinal ganglion cell encountering an axon of a sympathetic axon in culture. These studies demonstrate that just the briefest contact from a single filopodium is all that is necessary to elicit this aversive behavior, strongly suggesting that growth cones sense a repulsive signal on the surface of the other axon. By pairing different types of explants in such cultures and observing the growth cone interactions, a variety of different collapsing activities effective on different types of growth cones were discovered, showing that there is a rich heterogeneity of repulsive interactions between neurons (Kapfhammer and Raper, 1987b). Attempts to purify collapsing factors biochemically were aided by a bioassay in which reconstituted membrane vesicles were added to cultures of axons growing on laminin substrates. The first factor isolated in this way was a glycoprotein that could cause growth cone collapse, initially called Collapsin (Luo et al. Collapsin turned out to be a member of a large molecular family, the Semaphorins, and became known as Sema3A. The first member of the Semaphorin family to be identified, SemaI, came from grasshoppers (Kolodkin et al. Semal is also expressed at segment borders on the limb bud epithelium, and antibodies that neutralize SemaI function in the limb allow the Ti1 pioneers to cross segment borders that they normally would not, suggesting that this molecule normally serves a repellent function in vivo. In vertebrates, many peripheral target tissues express Semas, particularly Sema3A, and when Sema3A is knocked out, or when the Sema-receptors, Neuropilin, or Plexin, are knocked out, there is strong overgrowth of projections from both motor and sensory nerves into peripheral targets (Taniguchi et al. An interesting wrinkle concerning repulsive guidance is that the receptor for this cue must first bind the repellent molecule before turning away from it. Middle, intersomitic projections of spinal nerves, and bottom, projections into the limb, are all overgrown in mutant mice. In such cases, one might imagine that, if the affinity is high enough, the axon would attach rather than be repelled. The first is extracellular protein clipping in which the ectodomains of activated receptors are attacked by metalloproteases and cleaved, breaking the attachment between the growth cone and its substrate (Hattori et al. The second is endocytosis in which the entire receptor-ligand complex is internalized into the growth cone (Zimmer et al. In each case, the molecular bonds holding the growth cone to the repellent surface are neutralized, allowing the growth cone to retract. Slit is responsible for the guidance of olfactory tract axons away from the septum. It is the vertebrate homologue of a Drosophila protein, also called Slit, which is the ligand for the receptor Robo (Li et al. Motor neurons of the vertebrate spinal cord also express Robo and grow away from the ventral midline, which expresses Slit (Brose et al.
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