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The presence of these basic amino acids renders the protein susceptible to proteases from many different types of tissues and allows extrapulmonary dissemination due to broadened tissue tropism (Yuen 2005) order viagra super active 50 mg visa. Another explanation may be that interferons are pivotal in preventing viral spread outside the respiratory tract and that H5N1 interferes with this innate defence against viral infection generic viagra super active 25 mg online. The Virus Infectious diseases are the result of a conflict of interest between macroorganisms and microorganisms cheap viagra super active 50 mg fast delivery. Requirements for Success To become a pandemic strain, an influenza virus must comply with a series of re- quirements. It has to The Virus 25 • enter the human body and replicate there, • cause illness in humans, and • be easily transmittable between humans. In the current situation, the potential pandemic virus would have to compete with the al- ready circulating H3N2 and H1N1 strains. The prerequisite for success is good adaptation: adaptation to human cells; the ca- pability to take over the production machinery of the host cell to produce new off- spring; as well as making the individual cough and sneeze to spread the offspring viruses. The clue to success is virulence (Noah 2005, Obenauer 2006, Salomon 2006) – and novelty: if the virus is a true newcomer, most living human beings will have little or no protection at all. The new virus will have unlimited access to virtu- ally every human being and will find a feeding ground of > 6. The passing of powers from one reigning influenza subtype to a new one is called “antigenic shift” because the antigenic characteristics of the new virus need to shift dramatically to elude the immune system of virtually the entire mankind. Antigenic shift is a major change in the influenza A viruses resulting in new haemagglutinin and/or new neuraminidase proteins. This change may occur by: 1) reassortment of the segmented genome of two parent viruses, or 2) gradual mutation of an animal virus. For reassortment to take place, both the new pandemic candidate virus, nor- mally of avian origin, and an already circulating human virus, i. Inside the cell, genes from both viruses are reassembled in an entirely new virus (they don’t actually have sex, but for didactic purposes, this image might work quite nicely). Recent evi- dence with recombinant viruses containing genes from the 1918 pandemic virus shows that viruses expressing one or more 1918 virus genes were less virulent than the constellation of all eight genes together (Tumpey 2005). The 1918 virus was particular indeed: it appears that it was not the result of a reassortment of two ex- isting viruses, but an entirely avian-like virus that gradually adapted to humans in stepwise mutations (Taubenberger 2005). It is obviously tempting to speculate that the emergence of a completely new human-adapted avian influenza virus in 1918 (n=1) could be deadlier than the introduction of reassortant viruses in 1957 and 1968 (n=2), but such speculation is not scientific. Interestingly – and worryingly –, some amino acid changes in the 1918 virus that distinguish it from standard avian sequences are also seen in the highly pathogenic avian influenza virus strains of H5N1, suggesting that these changes may facilitate virus replication in human cells and increase pathogenicity (Taubenberger 2005). They are spherical or filamentous in structure, ranging from 80 to 120 nm in diameter (Figure 4 and 5). When sliced transversely, influenza virions resemble a symmetrical pepperoni pizza, with a circular slice of pepperoni in the 26 Influenza 2006 middle and seven other slices evenly distributed around it (Noda 2006). The domestic duck in Southeast Asia is the principal host of influenza A viruses and also has a central role in the generation and maintenance of the H5N1 virus (Li 2004). In Thailand, there was a strong association between the H5N1 virus and the abundance of free-grazing ducks and, to a lesser extent, native chickens and cocks, as well as wetlands, and humans. The virus is killed by heat (56°C for 3 hours or 60°C for 30 minutes) and common disinfectants, such as formalin and iodine compounds. Transmission Influenza is primarily transmitted from person to person via droplets (> 5 µm in diameter) from the nose and throat of an infected person who is coughing and sneezing (Figure 6). Particles do not remain suspended in the air, and close contact (up to 3–6 feet) is required for transmission. Transmission may also occur through direct skin-to-skin contact or indirect contact with respiratory secretions (touching contaminated surfaces then touching the eyes, nose or mouth). Individuals may spread influenza virus from up to two days before to approximately 5 days after onset of symptoms. Avian influenza viruses bind to cell-surface glycoproteins containing sialyl-galactosyl residues linked by a 2-3-linkage, whereas human viruses bind to receptors that contain terminal 2-6-linked sialyl-galactosyl moieties. For an avian virus to be easily transmitted between humans, it is fundamental that it acquires the ability to bind cells that display the 2-6 receptors so that it can enter the cell and replicate in them. While single amino acid substitutions can significantly alter re- ceptor specificity of avian H5N1 viruses (Gambaryan 2006), it is presently un- known which specific mutations are needed to make the H5N1 virus easily and sustainably transmissible among humans, but potential routes whereby H5N1 might mutate and acquire human specificity do exist (Stevens 2006). Apart from H5N1, human infection generally resulted in mild symptoms and rarely in severe illness (Du Ry van Beest Holle 2003, Koopmans 2004). H5N1: Making Progress At the moment, H5N1 infection in humans is relatively rare, although there must have been widespread exposure to the virus through infected poultry. This in an indicator that the species barrier to the acquisition of this avian virus is still quite high for H5N1 – despite having been in circulation for nearly 10 years. However, over the past years, H5N1 strains seem to have become more pathogenic and to have expanded their range of action: Individual Management 29 • The H5N1 influenza strain continues to evolve (Li 2004), and some clones have broader binding properties which may reflect a certain degree of adapta- tion in human hosts (Le 2005). H5N1 has expanded its host range not only in avian species (Perkins 2002), but also in mammals, naturally infecting humans, tigers, leopards, domestic cats and a stone marten (Keawcharoen 2004, Thanawongnuwech 2005, Amonsin 2006). However, when fed with H5N1 virus-infected chickens, cats developed severe disease and trans- mitted the virus to other cats (Kuiken 2004). Cats may excrete virus not only via the respiratory tract but also via the digestive tract (Rimmelzwaan 2006), suggesting that spread by potentially novel routes within and between mam- malian hosts might be possible. In influenza manage- ment, this one-line medical wisdom theoretically translates as: 1) three prophylaxis defence lines (exposure prophylaxis, vaccination, prophylactic use of antiviral drugs); and 2) one treatment defence line (antiviral drugs). Due to the very nature of influenza infection – infected individuals may be infectious for as long as 24– 48 hours before the onset of symptoms – exposure prophylaxis is virtually impossible during an ongoing epidemic or pandemic, especially in our highly 30 Influenza 2006 during an ongoing epidemic or pandemic, especially in our highly mobile and densely populated world. Epidemic Prophylaxis Exposure Prophylaxis Basic personal hygiene measures, invented more than a century ago, are still the cornerstones of prophylaxis. Vaccination Vaccination against influenza viruses is the second cornerstone in preventing influ- enza. Recommendations regarding the composition of the vaccine are issued yearly on the basis of detailed investigations of circulating strains. The rate of influenza vaccination depends on a number of variables, including explicit physician recommendation and media coverage (Ma 2006). In healthy primed adults, the efficacy after one dose may be as high as 80-100 %, while in unprimed adults (those receiving their first influenza immunisation), effi- cacy is in this range after two doses. The evidence of efficacy and effectiveness of influenza vaccines in individuals aged 65 years or older has recently been reviewed. Well matched vaccines prevented hospital admission, pneumonia, respiratory diseases, cardiac disease, and death. The effectiveness is better in people living in homes for the elderly than in elderly indi- viduals living in the community (Jefferson 2005). Inactivated vaccine reduces exac- erbations in patients with chronic obstructive pulmonary disease (Poole 2006). In- fluenza vaccines are efficacious in children older than two years but little evidence is available for children under two (Smith 2006). Nasal spray of live vaccines seemed to be better at preventing influenza illness than inactivated vaccines. Antiviral Drugs In selected populations, antiviral drugs may be a useful option in those not covered or inadequately protected by vaccination. It should be emphasised, though, that the prophylactic use of available antiviral drugs is by no means a substitute for the yearly vaccination recommended by national health services.

The results indicated that to successfully contain an epidemic buy viagra super active discount, health officials would need to find the first flu cases fast and implement a combination of public health measures very quickly buy viagra super active 50 mg visa. C H A P T E R 5 21st­Century Genetics edicine has evolved tremendously since practices like opening the vein of a sick person M the earliest human civilizations purchase viagra super active 25mg, when and draining off quarts of precious blood! Limited One of them, the Italian artist­inventor Leonardo scientific knowledge led to seemingly bizarre da Vinci, created beautiful and accurate By the end of the 16th century, anatomy was a common focus for scien­ tific scholars. Bacillus anthracis (left) causes anthrax focused on the practice of dissection, and Vibrio cholerae (below) causes cholera. During this time, scientists discovered that bacteria—not evil spirits or other imaginary One of today’s challenges is to map the entities—caused human diseases like cholera, actions and interactions of all these molecules, anthrax and tuberculosis. Genetic and genomic occurred in the 20th century, accelerated the research is helping scien­ study of all these areas of science. Now, at tists tackle many the start of the 21st century, opportunities questions in this have never been greater for turning scientific area. Without even organs in action, thinking, we sweat to maintain body tempera­ scientists hope to ture, get hungry when we need energy and feel learn how these tired when we need to sleep. Those who work at the intersection of computer science and biology often combine and analyze data from many different sources, look­ ing for informative patterns. Through an approach known as knowledge engineering, Rzhetsky and his team write computer programs that scan the contents The program first scans scientific papers of thousands of published scientific papers. Next, it evaluates the search GeneWays, focuses mainly on research literature results and makes sure they don’t overlap. They do know that jellyfish essential to modern don’t flash at each other in the dark, nor do they cell biology experiments glow continuously. Fruit fly sperm cells glow bright green when they of the millions of proteins major role in advancing the study of genes and express the gene for green fluorescent protein. The information then goes to a database that Rzhetsky and other scientists use to build large networks of molecular interactions. Rzhetsky and his team used GeneWays to iden­ tify risk genes for Alzheimer’s disease, a complex condition thought to be caused by many factors. In analyzing the data, Rzhetsky found important “nodes,” molecules that play key roles in the dis­ ease gene network that GeneWays modeled. These predicted molecular interactions were later confirmed by other researchers working in a lab, underscoring the value of computer model­ ing as a way to learn more about the molecular basis of disease. Andrey Rzhetsky uses the computer program GeneWays to locate important “hubs” of activity (large spheres) within massive gene networks. It’s important to realize that, in most cases, genetic information cannot offer definitive proof that a disease will occur. But if you have a very strong family history of breast cancer, for exam­ ple, there may be a faulty gene in your family that Hard Questions increases your risk of getting the disease. If you carry either of est dilemmas to emerge from this research is a these gene variants, your lifetime risk of getting social and ethical one. That is, how should people breast cancer is significantly higher than it would make use of information about their own genes? These concerns Only about 5 percent of all breast cancer include the potential for discrimination on the can be traced to a known, inherited gene basis of a person’s risk of disease or susceptibility variant. For example, you might health information from being used or shared want to begin getting mammograms or other without your knowledge. If cancer is found The New Genetics I 21st­Century Genetics 79 very early, it is usually more treatable, and the this gene can cause the disease, and those are odds for a cure are much higher. Currently, diagnostic laboratories across the How can there be 30 different variants of United States offer genetic tests for almost 2,000 one gene? Perhaps the most well­known example of nucleotides produces one variant, a change in a chromosome problem is Down syndrome, in another produces another variant, and so on. So the standard chromosome abnormality, or even by one gene genetic screening test for this disease scans for variant. Cystic fibrosis, for example, is due to a all of the more than 30 variants known to cause faulty gene, but more than 30 different variants of cystic fibrosis. Even years from now, when One thing you might consider is whether you researchers know more about the molecular could do something with what you learn from roots of disease, genetic tests will rarely provide a genetic test. In most cases, they won’t even You’ve already read about what you could provide “yes” or “no” answers. But what about a predict whether a person’s risk of getting a disease condition that shows up in middle­aged or older is relatively high, low or somewhere in between. Good Advice Since the story of genes and health is so complicated and is likely to stay that way for a while, it is very important to consider genetic information in context. Health care professionals known as genetic counselors can be a big help to people who are thinking about getting a genetic test. In addition to identifying suspects Genetic fingerprinting is not limited who leave traces at the scene of a crime to people. It can find small but poten­ (for example, strands of hair, drops of tially deadly traces of disease­causing bacteria in food or water, determine whether an expensive horse was sired by a Kentucky Derby winner or figure out whether a puppy’s parents were first cousins. The chances of a molecular fingerprint being the same in two people or two organisms are vanishingly small. Genetic counselors do their work Is a person who gave a blood or tissue sample in many different settings, including hospitals, entitled to profits from a company that develops private clinics, government agencies and uni­ a drug based on genetic information in her sam­ versity laboratories. An interesting aspect of the job is that genetic Can a blood or tissue sample that was donated counselors address the needs of entire families, for one purpose be used for an entirely different rather than just individual patients. Many of the most Field Study The word most often used to refer to This usually involves transferring genetic mate­ applications of genetic research, espe­ rial from one kind of organism into another. Using cially those leading to products for the same techniques that were developed for put­ human use, is biotechnology. It ting genes into animals for research purposes, involves techniques that use living scientists can create crop plants with desirable organisms—or substances derived traits, such as improved flavor or better resistance from those organisms—for various to insect pests. Transferring specific genes is practical purposes, such as making a faster and more efficient than traditional breeding biological product. One major application of biotech ­ The United States is home to far more geneti­ nology is in agriculture. Actually, this is cally modified crops than anywhere else in the hardly new: Humanity has engaged in world. In 2009, 85 percent of the country’s corn, agricultural biotechnology for 10,000 88 percent of its cotton and 91 percent of its soy­ years or more. Many traditional farming beans were cultivated from seeds genetically practices, from plant breeding to animal modified to resist plant pests and certain herbi­ husbandry, are really forms of biotech­ cides used to control weeds. Many believe that agricultural biotechnology is But in today’s agricultural industry, an important driver for improving world health. Traditionally, when an inventor comes up with a new idea and wants to sell it—whether it’s a radio­controlled toy boat or a customized laboratory chemical—he or she submits an appli­ cation to the U. Patents give inventors time to optimize their products and control how their inventions are used, allowing them to make money from their creativity. But opposition from farmers and consumers within and outside the United States has clouded agricultural biotechnology’s future.

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Antiviral Drugs Of the four antiviral drugs currently available for the treatment of influenza A in- fection (two neuraminidase inhibitors and two M2 ion channel inhibitors) purchase cheap viagra super active on line, only the neuraminidase inhibitors oseltamivir and zanamivir are also active against influ- enza B cheap viagra super active 50mg overnight delivery. All drugs are most effective if started within a few hours of the onset of symptoms and are generally licensed for use within 48 hours of the first symptoms cheap viagra super active 100mg visa. They can modify the severity of illness, as well as reducing the intensity of influ- enza symptoms and decreasing the duration of illness by about 1 to 3 days. How- ever, the extent to which antiviral treatment leads to a reduction of serious compli- cations and hospitalisation is still subject to debate. Treatment success is, in part, a variable of the time between the onset of symptoms and the beginning of antiviral treatment: the sooner after onset treatment begins, the better. The neuraminidase inhibitors, oseltamivir and zanamivir, have fewer side effects than the M2 ion channel inhibitors rimantadine and amantadine, and drug resistance seems to develop less frequently. The clinical pharmacology, adverse effects and resistance profiles of these drugs are discussed in detail in the Drugs chapter. Neuraminidase Inhibitors These drugs – introduced in 1999 and 2000 – interfere with the normal function of the influenza neuraminidase by mimicking sialic acid, the natural substrate of the Antiviral Drugs 171 neuraminidase (Varghese 1992, Varghese 1995). The viral neuraminidase is re- sponsible for cleaving sialic acid residues on newly formed virions, playing an es- sential role in their release and facilitating virus spread within the respiratory tract. When exposed to neuraminidase inhibitors, the influenza virions aggregate on the surface of the host cell, limiting the extent of infection within the mucosal secre- tions (McNicholl 2001) and reducing viral infectivity (see Figure at http://content. Experimental evidence further suggests that influenza neuraminidase may be essential at the early stage of virus invasion of the ciliated epithelium of human airways (Matrosovich 2004). The design of the neuraminidase inhibitors was a result of the analysis of the three- dimensional structure of influenza neuraminidase which disclosed the location and structure of the catalytic site (Colman 1983). Numerous treatment studies in healthy adults have shown that neuraminidase in- hibitors, when taken within 36 to 48 hours after the onset of symptoms, decrease the symptomatic illness by one or two days (Hayden 1997, Monto 1999, Treanor 2000, Nicholson 2000, Hedrick 2000, Cooper 2003, Whitley 2001, Aoki 2003). When started within the first 12 hours following the onset of fever, neuraminidase inhibitors shortened the illness by more than three days, in comparison to treatment that was started at 48 hours. The duration of fever, severity of symptoms, and time to return to normal activity also correlated with the time of initiation of antiviral intervention. A study in Canadian long-term care facilities showed that older nursing home resi- dents who were treated with oseltamivir within 48 hours after the onset of symp- toms were less likely to be prescribed antibiotics, to be hospitalised, or to die (Bowles 2002). Another study sug- gested that oseltamivir treatment of influenza illness reduces lower respiratory tract complications, antibiotic use, and hospitalisation in both healthy and “at-risk” adults (Kaiser 2003). Prevention trials have shown that neuraminidase inhibitors administered prophy- lactically reduce the risk of developing influenza by 60-90 % when given at the start of the influenza outbreak (Monto 1999b, Cooper 2003). When administered prophylactically to household contacts of an influenza index case, protective effi- cacy against clinical influenza was generally > 80 % (Hayden 2000, Kaiser 2000, Welliver 2001, Monto 2002). In par- ticular, the observed safety profile of oseltamivir and zanamivir compares favoura- bly with the M2 inhibitors rimantadine and amantadine (Freund 1999, Doucette 2001). Zanamivir is therefore not generally recommended for the treatment of patients with underly- 172 Treatment and Prophylaxis ing airways disease, and should also be discontinued in patients who develop bron- chospasm or who have a decline in respiratory function (Relenza 2003). In oseltamivir, competitive inhibition of excretion by the renal tubular epithelial cell anionic transporter may occur. Naturally occurring virus strains resistant to neuraminidase inhibitors are believed not to exist in human influenza A (McKimm-Breschkin 2003). However, a recent report describes a resistant H5N1 strain carry- ing the H274Y mutation causing viremia in two patients who subsequently died from avian influenza (de Jong 2005). Zanamivir seems to retain in vitro activity against some oseltamivir-resistant strains (McKimm-Breschkin 2003, Mishin 2005). Following clinical use, the incidence of development of resistant strains is lower among adults and adolescents older than 13 years, than among children. These findings are reason for concern, since children are an important transmission vector for the spread of influenza virus in the community. In the case of an H5N1 pandemic, the frequency of resistance emergence during osel- tamivir treatment of H5N1 paediatric patients is uncertain, but it is likely to be no less than that observed in children infected with currently circulating human influ- enza viruses (Hayden 2005). Neuraminidase inhibitors are effective against the virus that caused the 1918 pan- demic (Tumpey 2002). Indications for the Use of Neuraminidase Inhibitors ® ® Oseltamivir (Tamiflu ) and zanamivir (Relenza ) are currently licensed for the treatment of influenza A and B. They should be used only when symptoms have occurred within the previous 48 hours and should ideally be initiated within 12 hours of the start of illness. In addition, oseltamivir – but not zanamivir (with the exception of two countries) – is also licensed for prophylaxis when used within 48 hours of exposure to influ- enza and when influenza is circulating in the community; it is also licensed for use in exceptional circumstances (e. Oseltamivir and zanamivir seem to have similar efficacy, but they differ in their modes of delivery and tolerability. Zanamivir is delivered by inhalation and is well tolerated; however, children, especially those under 8 years old, are usually unable to use the delivery system appropriately and elderly people may have difficulties, too (Diggory 2001). Antiviral Drugs 173 M2 Ion Channel Inhibitors Amantadine and rimantadine are tricyclic symmetric adamantanamines. They are active only against influenza A virus (influenza B does not possess an M2 protein), have more side effects than neuraminidase inhibitors, and may select for readily transmissible drug-resistant viruses. M2 inhibitors block an ion channel formed by the M2 protein that spans the viral membrane (Hay 1985, Sugrue 1991) and is required for viral uncoating (for more details see the Drugs chapter). Both drugs are effective as treatment if started within 24 hours of illness onset, reducing fever and symptoms by 1–2 days (Wing- field 1969, Smorodintsev 1970, van Voris 1981). Daily prophylaxis during an influenza season reduces infection rates by 50–90 % (Dawkins 1968, Dolin 1982, Clover 1986). In one study, rimantadine was ineffective in pro- tecting household members from influenza A infection (Hayden 1989). In addition, amantadine has a wide range of toxicity which may be in part attributable to the anticholinergic effects of the drug. The same frequency of side effects was found when the drug was tested in young healthy volunteers over a four-week period. Among 44 individuals, side effects (dizziness, nervousness, and insomnia) were well tolerated by most subjects, but 6 volunteers discontinued amantadine because of marked complaints. When studied in 450 volunteers during an outbreak of influenza A, the prophylactic effects of rimantadine and amantadine were comparable. Influ- enza-like illness occurred in 14 % of the rimantadine group and in 9 % of the amantadine group (Dolin 1982). Withdrawal from the study because of central nervous system side effects was more frequent in the amantadine (13 %) than in the rimantadine group (6 %). The potential for drug interactions is greater for amantadine, especially when co- administered with central nervous system stimulants. Agents with anticholinergic properties may potentiate the anticholinergic-like side effects of amantadine. Point mutations in the M gene lead to amino acid changes in the transmembrane region of the M2 protein and may confer high-level resistance to amantadine. The genetic basis for resistance appears to be single amino acid substitutions at positions 26, 27, 30, 31 or 34 in the transmembrane portion of the M2 ion channel (Hay 1985). In an avian model, they were also genetically stable, showing no reversion to the wild- type after six passages in birds over a period of greater than 20 days (Bean 1989).

These breakdown products then pass through capillary walls to be used for energy by cells or stored in adipose tissue as fat 100mg viagra super active overnight delivery. Liver cells combine the remaining chylomicron remnants with proteins purchase viagra super active 100mg with amex, forming lipoproteins that transport cholesterol in the blood cheap viagra super active 25 mg amex. Nucleic Acid Absorption The products of nucleic acid digestion—pentose sugars, nitrogenous bases, and phosphate ions—are transported by carriers across the villus epithelium via active transport. Since electrolytes dissociate into ions in water, most are absorbed via active transport throughout the entire small intestine. During absorption, co- transport mechanisms result in the accumulation of sodium ions inside the cells, whereas anti-port mechanisms reduce the potassium ion concentration inside the cells. Iron and calcium are exceptions; they are absorbed in the duodenum in amounts that meet the body’s current requirements, as follows: Iron—The ionic iron needed for the production of hemoglobin is absorbed into mucosal cells via active transport. Once inside mucosal cells, ionic iron binds to the protein ferritin, creating iron-ferritin complexes that store iron until needed. When the body has enough iron, most of the stored iron is lost when worn-out epithelial cells slough off. When the body needs iron because, for example, it is lost during acute or chronic bleeding, there is increased uptake of iron from the intestine and accelerated release of iron into the bloodstream. Since women experience significant iron loss during menstruation, they have around four times as many iron transport proteins in their intestinal epithelial cells as do men. Vitamin Absorption The small intestine absorbs the vitamins that occur naturally in food and supplements. Fat-soluble vitamins (A, D, E, and K) 1138 Chapter 23 | The Digestive System are absorbed along with dietary lipids in micelles via simple diffusion. Most water-soluble vitamins (including most B vitamins and vitamin C) also are absorbed by simple diffusion. Intrinsic factor secreted in the stomach binds to vitamin B12, preventing its digestion and creating a complex that binds to mucosal receptors in the terminal ileum, where it is taken up by endocytosis. Water absorption is driven by the concentration gradient of the water: The concentration of water is higher in chyme than it is in epithelial cells. The organs of the alimentary canal are the mouth, pharynx, esophagus, stomach, small intestine, and large intestine. The accessory digestive structures include the teeth, tongue, salivary glands, liver, pancreas, and gallbladder. The wall of the alimentary canal is composed of four basic tissue layers: mucosa, submucosa, muscularis, and serosa. The enteric nervous system provides intrinsic innervation, and the This OpenStax book is available for free at http://cnx. The six activities involved in this process are ingestion, motility, mechanical digestion, chemical digestion, absorption, and defecation. The pharynx, which plays roles in breathing and vocalization as well as digestion, runs from the nasal and oral cavities superiorly to the esophagus inferiorly (for digestion) and to the larynx anteriorly (for respiration). During deglutition (swallowing), the soft palate rises to close off the nasopharynx, the larynx elevates, and the epiglottis folds over the glottis. The esophagus includes an upper esophageal sphincter made of skeletal muscle, which regulates the movement of food from the pharynx to the esophagus. It also has a lower esophageal sphincter, made of smooth muscle, which controls the passage of food from the esophagus to the stomach. It secretes gastric juices that break down food and absorbs certain drugs, including aspirin and some alcohol. It stores food as an acidic liquid called chyme, and releases it gradually into the small intestine through the pyloric sphincter. These two activities are facilitated by structural adaptations that increase the mucosal surface area by 600-fold, including circular folds, villi, and microvilli. There are around 200 million microvilli per square millimeter of small intestine, which contain brush border enzymes that complete the digestion of carbohydrates and proteins. Combined with pancreatic juice, intestinal juice provides the liquid medium needed to further digest and absorb substances from chyme. The mucosa of the large intestinal wall is generously endowed with goblet cells, which secrete mucus that eases the passage of feces. Bile contains bile salts and phospholipids, which emulsify large lipid globules into tiny lipid droplets, a necessary step in lipid digestion and absorption. The pancreas produces the enzyme- and bicarbonate-rich pancreatic juice and delivers it to the small intestine through ducts. Pancreatic juice buffers the acidic gastric juice in chyme, inactivates pepsin from the stomach, and enables the optimal functioning of digestive enzymes in the small intestine. Chemical digestion breaks large food molecules down into their chemical building blocks, which can then be absorbed through the intestinal wall and into the general circulation. Intestinal brush border enzymes and pancreatic enzymes are responsible for the majority of chemical digestion. With the help of bile salts and lecithin, the dietary fats are emulsified to form micelles, which can carry the fat particles to the surface of the enterocytes. There, the micelles release their fats to 1146 Chapter 23 | The Digestive System diffuse across the cell membrane. The fats are then reassembled into triglycerides and mixed with other lipids and proteins into chylomicrons that can pass into lacteals. Other absorbed monomers travel from blood capillaries in the villus to the hepatic portal vein and then to the liver. Along the way, note how the food changes digestion and absorption of nutrients and transport these consistency and form. By watching this animation non-fat nutrients from the small intestine to their release as (http://openstaxcollege. Of the swallowing) to see how swallowing is a complex process three major food classes (carbohydrates, fats, and proteins), that involves the nervous system to coordinate the actions which is digested in the mouth, the stomach, and the small of upper respiratory and digestive activities. At rest, about 1500 mL of how this structure functions in the initiation of protein blood per minute flow through the liver. Describe unique anatomical features that enable the of helping to protect the body against disease, and through stomach to perform digestive functions. Walking delivered to the small intestine slowly and in small past a bakery, you catch a whiff of freshly baked bread. Discuss how saliva produced by the parotid gland differs in action from saliva produced by the sublingual gland. Why does the pancreas secrete some enzymes in their inactive forms, and where are these enzymes activated? During a hockey game, the puck hits a player in the mouth, knocking out all eight of his most anterior teeth. Describe the location of hepatocytes in the liver and Which teeth did the player lose and how does this loss how this arrangement enhances their function. Many factors contribute to overall metabolism, including lean muscle mass, the amount and quality of food consumed, and the physical demands placed on the human body. You may have been told since childhood to start the day with a good breakfast to give you the energy to get through most of the day.

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A study of primary especially cost effective buy cheap viagra super active online, given that the smoking- care screening and brief physician intervention attributable medical care needed by infants for adult risky drinkers yielded a net benefit of 56 whose mothers smoked while pregnant is an $947 per person discount viagra super active 100 mg with mastercard. A one- percent reduction in the prevalence of smoking The use of screening and brief interventions in in the U generic 100 mg viagra super active visa. A study of screening and brief § low-birth weight births by 2,000, resulting in interventions for risky alcohol use among adults $21 million in avoided direct medical costs. In The American Legacy Foundation projected that total, the implementation of a hospital-based a reduction in Medicaid costs of nearly one alcohol screening and brief intervention program ** billion dollars could be achieved by preventing for risky alcohol use was estimated to reduce †† the current cohort of 24-year-olds from health care costs by $3. Brief interventions with adolescents were successful in motivating all Medicaid ages 18 and 19 who were admitted to a trauma recipients who smoke to quit, states’ Medicaid center for alcohol-related injuries also have been expenditures would be, on average, 5. An alcohol intervention program costing For 45-year old men with a 10-year risk for $50,000 that could successfully prevent at least coronary heart disease of 7. Consisting of two doctor visits and two nurse † Costs include individually-tailored diet and exercise follow-up calls. Significant declines were seen in hospital stays, generating billions of dollars areas such as the number of inpatient 61 hospital days and emergency department in largely avoidable health care charges. Some research suggests that treatment alcohol or drugs other than nicotine who “pays for itself,” often on the day it is delivered were enrolled in an outpatient treatment † and the total cost savings from addiction program with a control group found that 63 treatment continue to accrue over time. The study 64 are greater than the cost of treatment, also found that treatment can cut health care administrators and policymakers too often costs associated with addiction by about one disregard benefits of treatment that accrue quarter, primarily by reducing the number of beyond the narrow silo of each individual annual hospital stays and the likelihood of 67 government program. The one exception was opioid associated with an annual $2,500 reduction ** maintenance therapy which paid for itself in in medical expenses among adult patients health care savings. Following the implementation of Medicaid- covered pharmaceutical therapy for addiction  A performance audit of the costs and involving nicotine, Massachusetts had a 46 savings to the Colorado Medicaid Program-- percent annual decrease in hospitalizations for which in 2006, implemented a benefit to heart attacks and a 49 percent annual decrease in †† 74 provide outpatient addiction treatment for cases of coronary atherosclerosis. Those in the control group depending on the modality of treatment were more likely to have an alcohol-related visit (with long-term residential treatment to the emergency department during the study yielding the greatest reduction in recidivism, compared to patients taking naltrexone (15 72 76 roughly 27 to 34 percent). One study Measured as receiving a clinical diagnosis of alcohol or other drug dependence or psychosis, examined the cost effectiveness of providing receiving detoxification services or having been referred for alcohol or other drug assessment by the state division of alcohol and substance abuse. There were, however, no significant changes in ‡ Analysis based on available Medicaid claims data, rates of hospital admissions for respiratory conditions not a controlled longitudinal study. Recently-enacted federal and state parity laws An examination of health care and pharmacy have expanded coverage for addiction treatment costs for patients with addiction involving where offered, and the Patient Protection and opioids in a large U. Another study projected Federal and state parity laws require private that methadone maintenance therapy costs ‡ 80 insurers that provide mental health and addiction $5,915 for every year of life gained. In general, restrictions placed capacity for heroin users is cost effective, at on addiction services (e. Employers including addiction benefits in 97% 97% * most popular plan This includes traditional and benchmark/benchmark Employers placing equivalent managed care plans. Even if they are married, in school or eligible to † Including new small fully-insured or self-insured enroll in their employer’s plan. These services Impede Comprehensive Addiction Care were reimbursed only when reasonable and 112 necessary to diagnose or treat illness or injury. Recent developments in Medicare would provide coverage in primary § Medicare and Medicaid reimbursement have care settings for preventive annual alcohol ** begun to remove some of the cost barriers that screening of all patients and up to four brief, health professionals faced in routinely screening face-to-face interventions for Medicare their patients for risky use of addictive beneficiaries who screen positive for risky substances and conducting early interventions alcohol use but who do not meet clinical criteria 106 113 when necessary. The Medicaid codes cover these services related to alcohol and other drugs screening, questions about tobacco use are 108 considered part of the medical history to be (excluding nicotine). These codes are available for health care providers in individual collected, for example, during the Initial states to use but there is no requirement for Preventive Physical Examination for those new 115 providers to use the codes. As of August 2010, Medicare determine which services are reimbursed and, to does cover preventive tobacco cessation be operational, states have to enable the billing counseling for smokers who do not present with * 109 signs or symptoms of tobacco-related disease. With regard to smoking, the only screening The benefit includes two individual tobacco services that states explicitly are required to cessation counseling attempts per year, with 116 provide are those that fall under the Early and each attempt consisting of up to four sessions. Medicare allows providers to choose any screening tool that is alcohol and other drugs (excluding nicotine) for appropriate for their clinical population and setting. A similar legal provision of individuals covered under Medicaid and allows many states to deny disability payments * 122 commercial insurance, but also allows states or workers’ compensation to individuals harmed facing budget deficits to scale back eligibility while under the influence of alcohol or while † 123 under certain circumstances. Because of participating in an illegal act, such as driving 130 economic constraints, states appear to be cutting under the influence. Current coverage of addiction treatment is not designed to prevent An additional resource problem that stands in and treat the disease effectively. States are counseling and/or psychotherapy, and free to choose whether or not to include tobacco 143 diagnosis, treatment, assessment and cessation benefits for other enrollees. Eight states covered group counseling for all Medicaid  Outpatient rehabilitation services, including enrollees, five covered group counseling only diagnostic and treatment services. States for enrollees in some programs (fee for service providing optional benefits under Medicaid or managed care) and five states covered group often choose this option since it does not counseling for pregnant women only. As of require services to be provided under the 2009, 34 states covered the nicotine patch for all direction of a physician and instead permits Medicaid enrollees, 33 covered bupropion, 32 the delivery of services including mutual covered nicotine gum, 32 covered varenicline, support by community paraprofessionals and 28 covered nicotine nasal spray, 27 covered 138 nicotine inhalers and 25 covered nicotine peers; 144 lozenges. As of 2011, six state Medicaid 139 programs provide comprehensive coverage for  Clinic services; and smoking cessation treatments for all Medicaid 140 enrollees, while five state Medicaid programs  Case management services. Last, states may provide addiction treatment services as part of a Medicaid managed care † 141 Medicare. Medicare covers the their eligibility requirements and benefits, following services, when medically necessary: individuals have substantially different access to care depending on the state in which they live. States  Tobacco cessation counseling from a that opt simply to expand their Medicaid qualified physician or practitioner for all * programs are required to follow the rules and smokers and tobacco cessation medications 157 151 requirements of Medicaid. States also may use a benefits package that is † Annual limits are caps that insurers place on the actuarially equivalent to one of the benchmark plans, benefits an enrollee is entitled to each year. Lifetime limits are caps on results in a cost increase of greater than two percent expenditures, on specific services or both during an in the first plan year and greater than one percent in individual’s lifetime. For some of those allowed visits or length of stay, however, does who were successful in becoming insured, co- not accord with best practices for treating cases insurance and co-payments rendered treatment 164 169 of addiction that are chronic and relapsing. Furthermore, coverage for for addiction treatment benefits were 170 mental health and addiction services varies unaffected. Yet arise from its passage, many limitations remain rather than defining what these services must both in policy and practice. As a result, individual market (“grandfathered”) health 173 care may transition toward outpatient plans. Within limits--the plan must be comparable to a In the years following, addiction treatment benchmark plan: (1) the largest plan by enrollment in admission rates did not increase significantly. If it is deemed unconstitutional and severable, then the prohibitions against excluding patients with pre-existing conditions and charging higher premiums based on a person’s medical history also might be invalidated. In spite of the evidence that risky use of addictive substances is a public health problem and addiction is a disease: *  Most health professionals are not sufficiently trained to educate patients about risky use and addiction, conduct screening and interventions for risky use or diagnose and treat addiction;  Most of those who currently are providing addiction treatment are not medical professionals and are not equipped with the knowledge, skills or credentials necessary to prove the full range of evidence-based † 1 services to address addiction effectively; and * The term “health professional” as used in this report includes medical professionals (physicians, physician assistants, nurses and nurse practitioners, dentists, pharmacists) and graduate-level clinical mental health professionals (psychologists, social workers, counselors). All health professionals can be trained to educate patients about risky use and addiction and screen for these conditions; brief interventions also can be conducted by appropriately trained health professionals. Diagnosis and treatment requires a trained physician with the exception of psychosocial treatments which can be provided by trained graduate-level clinical mental health professionals working with a managing physician. A nationally representative survey of accountability gap in addiction treatment is the addiction treatment facilities found that one- fact that there are no national standards; instead, quarter of the program directors were not full- there is considerable inconsistency among states time employees; only two of the programs in the regulation of individual treatment surveyed were directed by a physician; 54 providers and of the programs and facilities that percent employed a part-time physician; less * provide addiction treatment services. An older study found that medical addiction, treatment is provided within a highly- professionals and graduate-level counselors each regulated health care system. In contrast, made up only about 17 percent of the full-time patients with the disease of addiction are staff of addiction treatment facilities and that referred to a broad range of providers largely only 12.

People who consume high-starch/low- between 45 and 81% in areas with around 1 mg fluoride/L sugars diets generally have low caries experience whereas 1 water cheap 100 mg viagra super active fast delivery. Enamel fluorosis as well as skeletal fluorosis are people who consume low-starch/high-sugars diets have 75 found in large areas of India cheap viagra super active 25 mg visa, Thailand discount viagra super active 25mg without a prescription, in the Rift Valley of high levels of caries. In the Turku study intake of starch Starches and dental caries was not limited and all groups ate unlimited starch yet low Starch constitutes a heterogeneous food group and it caries occurred in the xylitol (sugar free) group. All these factors should be considered diet and dental caries in 11–12-year-old English children, when assessing the potential and relative cariogenicity of Rugg-Gunn et al. Some argue that cooked and processed starches starch and caries increment when controlling for sugars enter into the caries process because starches are broken intake. Children with high-starch and low-sugars intakes down by salivary amylase releasing glucose, maltose and had significantly fewer caries develop than children with 95 maltotriose and that these are metabolised by oral bacteria low starch/high sugars intake. The not good at discriminating the acidogenic potential intake of starch increased during this period in Norway 125 and Japan yet the occurrence of caries was reduced. Populations that habitually consume a remove plaque from all areas of the mouth and then high-starch/low-sugars diet have also been reported to 68,75,134,135 measure pH (harvesting method) are more discriminating have low levels of dental caries. For example and have shown that starch-containing foods are less the Chinese and Vietnamese, Ethiopians and South Diet, nutrition and prevention of dental diseases 215 American Indians have eaten cooked starches in the form in fruits. These studies have also used an indwelling of rice, wheat and maize but have a low sugars intake and plaque pH electrode that tends to give a hypersensitive 136 low caries levels. Animal studies have shown that, when fruit is well as comparing sugar availability and level of caries, consumed in high frequencies (e. However, when the have shown that, as habitually consumed, fruit is of low 79 data were reanalysed by Rugg-Gunn to control for sugar cariogenicity. For example, a number of cross-sectional availability the relationship between wheat availability studies have compared dental caries experience to levels 144 and dental caries disappeared. In 147 stimulate increased secretion of saliva, increasing its a study of longitudinal design, Clancy et al. Unrefined plant foods also contain negative association between caries increment over 1 year phosphates and there is some evidence that they convey a and the consumption of apples and fruit juice. The only 79 Rugg-Gunn extensively reviewed the evidence on the epidemiological study in which an association between relationship between starches and dental caries and fruit consumption and dental caries was reported was that 148 concluded that: of Grobler and Blignaut who compared the dental caries experience of workers on apple and grape farms. Finely ground and heat-treated starch can induce dental whereas the workers on the grape farms consumed on caries but the amount of caries is less than that caused average three bunches of grapes per day. Many highly Dried fruit may potentially be more cariogenic since the processed starchy foods are also relatively high in fats and drying process breaks down the cellular structure of the or free sugars and salt (e. He also concluded Fruit and dental caries that, on present evidence, increasing consumption of fresh In experimental conditions in which fruit is a major dietary fruit in order to replace ‘non-milk extrinsic sugars’ (free constituent, fruits may participate in the caries process; sugars) in the diet is likely to decrease the level of dental 79 however, as consumed as part of the mixed human diet caries in a population. A number of Novel carbohydrates and dental caries risk plaque pH studies have found fruit to be acidogenic Glucose polymers (glucose syrups and maltodextrins) 139,140 (though less so than sucrose) although the extent of comprise a mixture of short chain saccharides and alpha- 141 this varies according to texture and sugars content. When isolated from foods, suggest that maltodextrins and glucose syrups are phytate is an effective anti-caries factor but as an intrinsic 149–151 79 cariogenic. Plaque pH fibrous foods protect the teeth is because they mechani- studies and experiments in vitro suggest that isomaltoo- cally stimulate salivary flow. Other foods that are good ligosaccharides and glucooligosaccharides may be less gustatory and/or mechanical stimulants to salivary flow 152–154 acidogenic compared with sucrose. Plaque pH studies have shown that consuming cheese following a sugary snack virtually abolishes the usual fall Classification of sugars and carbohydrates for 157 in pH that is associated with sugars consumption. The calcium concentration of manufacturer, cook or consumer) but also includes sugars dental plaque strongly influences the balance between de- present in fruit juices, honey and syrups. In an epidemiological and general health purposes it is important to distinguish study, cheese intake was higher in children who remained between sugars naturally present in fruits, vegetables, caries-free over a 2-year period than in those who grains and milk as the evidence shows that these foods are 95 developed caries. The consumption of 158 leagues , in a controlled clinical trial in children, these foods is also desirable, whereas the consumption of demonstrated that eating a 5 g piece of hard cheese foods rich in free sugars is not. If the intake of free sugars daily, following breakfast, for a period of 2 years, resulted were limited and the intake of fruit, vegetables, whole- in the development of significantly less caries. Several studies have shown that the fall in plaque Is there an inverse relationship between the intake 159,160 pH following cows’ milk consumption is negligible. There is some evidence from animal studies that the It is important to consider the effect that changing one addition of cows’ milk to a cariogenic diet reduced the aspect of the diet has on other components of the diet. A few that have monitored dietary changes and the influence that specific case studies have linked prolonged ad libitum and changing one constituent has on other nutrients do not nocturnal breastfeeding to early childhood caries. Breast- support the hypothesis for an inverse relationship feeding has the advantage that it does not necessitate the between the intake of free sugars and fat. There is a use of a feeder bottle, which has been associated with growing body of evidence from such longitudinal research early childhood caries. A breastfed infant will also receive that shows that changes in intake of fat and sugar are not 168 milk of a controlled composition to which additional free inversely related. There are no benefits to dental sectional study, found that fat intake by adolescents health of feeding using a formula feed. Animal studies have looked at the effect of dietary intervention study to increase fibre intake, Cole- acidic food and drink consumption on demineralisation of 170 143 Hamilton et al. Miller inverse relationship between intake of free sugars and fat made the important observation that fruit juices were 3–10 and furthermore overall dietary goals that promote times more destructive than whole fruit in rats. However, increased intake of wholegrain staple foods, fruits and due to differences in drinking technique and salivary flow vegetables and a reduced consumption of free sugars are and composition, there are difficulties in extrapolating the unlikely to lead to an increased consumption in fat. Many of the reports on diet and erosion have been Diet and dental erosion single case reports and have shown that extensive erosion 179 The evidence for an aetiological role of diet in the has been associated with sucking lemon wedges , development of dental erosion comes from clinical trials, drinking cola continuously or holding cola in the 180,181 human observational studies, experimental clinical mouth , addition of baby fruit juices to comforters 182 studies, animal studies, case reports and experiments in or reservoir feeders , or mega doses of chewable 171 183 vitro. However, in general such studies have 172 shown that beverages with a high titratable acidity or a pH Stabholz et al. Fruit juices have also been 184 10–18 months and found that the teeth showed slight shown to be more erosive than pulped fruits. However, Meurman 21 association between dental erosion and the consumption and Cate argue that present data does not allow the of a number of acidic foods and drinks including frequent ranking of different acids. Levels observed in industri- beverages and foods is a more important determinant of alised countries are thought to be due to increased erosion than total amount consumed and also that erosion consumption of acidic beverages (i. Fruit juices are more erosive than whole fruits and tends to occur in individuals with good oral hygiene. Other risk factors reduce the prevalence of erosion the frequency of acidic included eating disorders (largely due to effect of intrinsic beverages needs to be reduced and/or the resistance to acids on vomiting), gastro-oesophageal reflux and a low erosion needs to be increased. The age-related increase was more comprehensive population-based studies on the greatest in the highest bands of soft drink consumption. The longitudinal patterns of the dental proportion who had erosion increased from 28 to 52% erosion in populations needs to be monitored and related between ages 7–10 and 11–14, whereas in the lowest to changes in dietary factors (e. Summary of the strengths and weaknesses of the Experimental clinical studies have shown that con- evidence sumption of, or rinsing with, acidic beverages significantly lowers the pH of the oral fluids and this is most marked The strength of the evidence linking dietary sugars to 141 with grapefruit juice. Enamel slab experiments have dental caries risk is in the multiplicity of the studies rather shown that enamel is softened within 1 hr of exposure to than the power of any individual study.

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Glycogenesis Glycogen storage diseases These are a group of genetic diseases that result from a defect in an enzyme required for either glycogen synthesis or degradation order viagra super active 100 mg fast delivery. They result in either formation of glycogen that has an abnormal structure or the accumulation of excessive amounts of normal glycogen in specific tissues buy viagra super active 50 mg on-line, A particular enzyme may be defective in a single tissue such as the liver or the defect may be more generalized order cheap viagra super active online, affecting muscle, kidney, intestine and myocardium. The severity of the diseases may range from fatal in infancy to mild disorders that are not life threatening some of the more prevalent glycogen storage diseases are the following. To provide the cell with ribose-5-phosphate (R5P) for the synthesis of the nucleotides and nucleic acids. The 3 carbon sugar generated is glyceraldehyde-3-phsphate which can be shunted to glycolysis and oxidized to pyruvate. Alternatively, it can be utilized by the gluconeogenic enzymes to generate more 6 carbon sugars (fructose-6-phosphate or glucose-6-phosphate). Although this bond plays a very important role in protein structure and function, inappropriately introduced disulfides can be detrimental. Oxidative stress also generates peroxides that in turn can be reduced by glutathione to generate water and an alcohol. Several deficiencies in the level of activity (not function) of glucose-6-phosphate dehydrogenase have been observed to be associated with resistance to the malarial parasite, Plasmodium falciparum, among individuals of Mediterranean and African descent. The basis for this resistance is the weakening of the red cell membrane (the erythrocyte is the host cell for the parasite) such that it cannot sustain the parasitic life cycle long enough for productive growth. Coris Cycle or Lactic Acid Cycle In an actively contracting muscle, only about 8% of the pyruvate is utilized by the citric acid cycle and the remaining is, therefore, reduced to lactate. The muscle cramps, often associated with strenuous muscular exercise are thought to be due to lactate accumulation. It is then taken up through gluconeogenesis pathway and becomes glucose, which can enter into blood and then taken to muscle. Significance of the cycle: Muscle cannot form glucose by gluconeogenesis process because glucose 6 phosphatase is absent. In the absence of dietary intake of carbohydrate liver glycogen can meet these needs for only 10 to 18 hours During prolonged fast hepatic glycogen stores are depleted and glucose is formed from precursors such as lactate, pyruvate, glycerol and keto acids. Approximately 90% of gluconeogenesis occurs in the liver whereas kidneys provide 10 % of newly synthesized glucose molecules, The kidneys thus play a minor role except during prolonged starvation when they become major glucose producing organs. Reactions Unique to Gluconeogenesis Seven of the reactions of glycolysis are reversible and are used in the synthesis of glucose from lactate or pyruvate. However three of the reactions are irreversible and must be bypassed by four alternate reactions that energetically favor the synthesis of glucose. Biotin is a coenzyme of pyruvate carboxylase derived from vitamin B6 covalently bound to the apoenyme through an ε-amino group of lysine forming the active enzyme. Elevated levels of acetyl CoA may signal one of several metabolic states in which the increased synthesis of oxaloacetate is required. It must first be reduced to malate which can then be transported from the mitochondria to the cytosol. Regulation by fructose 2,6- bisphoshate Fructose1, 6-bisphosphatase is inhibited by fructose 2, 6-bisphosphate, an allosteric modifier whose concentration is influenced by the level of circulating glucagons. Substrates for Gluconeogenesis Gluconeogenic precursors are molecules that can give rise to a net synthesis of glucose. Glycerol, lactate, and the α-keto acids obtained from the deamination of glucogenic amino acids are the most important gluconeogenic precursors. Glycerol is released during hydrolysis of triacylgycerol in adipose tissue and is delivered to the liver. Lactate is released in the blood by cells, lacking mitochondria such as red blood cells, and exercising skeletal muscle. Ketogenic compounds AcetylCoA and compounds that give rise to acetyl CoA (for example acetocetate and ketogenic amino acids) cannot give rise to a net synthesis of glucose, this is due to the irreversible nature of the pyruvate dehydrogenase reaction, (pyruvate to acetyl CoA. Understand the mechanism and effect of poisons on cellular energy generation Energy Generation and Utilization in the Living System I-Introduction Energy is vital to life. Most organisms obtain energy by oxidation of these fuel molecules Carbohydrates, fats and amino acids. Cellular oxidation of these molecules release energy, part of which is conserved through the synthesis of high-energy phosphate bonds and the rest is lost as heat. It is the universal transfer agent of chemical energy between energy-yielding and energy- requiring cellular processes. The hydrolysis of these high - energy phosphate bonds release energy which powers cellular energy requiring processes. Free energy change of a biological reactions is reported as the standard free energy change 0’ (ΔG ) 0’- ΔG is the value of ΔG for a reaction at standard conditions for biological reactions (pH 7, o 1M, 25 C, 1 atmosphere pressure) Free energy change is used to predict the direction and equilibrium of chemical reactions If ΔG is negative – net loss of energy (exergonic) - reaction goes spontaneously If ΔG is positive - net gain of energy (endergonic) reaction does not go spontaneously If ΔG is zero- reactants are in equilibrium C - Oxidation-Reduction Reactions The utilization of chemical energy in living system involves oxidation – reduction reactions. For example, the energy of chemical bonds of carbohydrates, lipids and proteins is released and captured in utilization form by processes involving oxidation- reductions. Determined by measuring the electromotive force generated by a sample half-cell with respect to standard reference half- cell Anegative E’o = lower affinity for electrons A positive E’o = higher affinity for electrons - H + 2e H2 E’o = - 0. In biological systems the primary electron donors are fuel molecules such as carbohydrates, fats and proteins. The free-energy change of an oxidation – reduction reaction can be calculated from the difference in reduction potentials of the reactants using the formula: O ΔG ’= - nFΔE’o Where n= 2 (No of electrons transferred) F= 23. This occurs by the help of energy conserving system in the inner mitochondrial membrane of eukaryotes or plasma membrane of prokaryotes. The fuel molecules are metabolized to a common intermediate called aceyl CoA which is further degraded by a common pathway called Kreb’s cycle. This metabolic pathway in addition to providing energy provides building blocks required for growth, reproduction, repair and maintenance of cellular viability. Structurally it is bounded by two separate membranes (outer mitochondrial membrane and inner mitochondrial membrane) Out membrane - smooth and unfolded - Freely permeable to most ions and polar molecules (Contain porous channels) Inner membrane - folded into cristae-increased surface area - Highly impermeable to most ions and polar molecules Contain transporters which access polar and ionic molecules in and out Cristae are characteristic of muscle and other metabolically active cell types - Protein-rich membrane (about 75%) Inter membrane space – space between outer and inner membranes Matrix-the internal compartment containing soluble enzymes and mitochondrial genetic material Fig 3. Inside matrix pyruvate is oxidized into acetylCoA by pyruvate dehydrogenase complex which is complex of E1, E2 and E3 enzymes. Considerable free energy is lost as heat due to hydrolysis of thisester bond (drive the reaction forward). Isomerization of citrate to isocitrate by aconitase Aconitase contains iron - sulfer (Fe:S) cluster that assists the enzymatic activity fluoroacetate (potent rodenticide) inhibits aconitase with the ultimate effect of blocking Kreb’s cycle and oxidative phosphorylation. Oxidative decarboxylation of α- ketoglutarate by α - ketoglutarate dehydrogenase complex α-ketoglutarate is structurally and functionally similar to pyruvate dehydrogenase complex of three enzymes (A’ B’ C’) 66 A’ (α - ketoglutarate dehydrogenase), B’ (transuccinylase), C’ (dihydrolipoyl dehydrogenase). Transfer and accept two electrons at a time Cytochromes – heme conjugated proteins 2+ 3+ Heme = Fe /F + porphyrin Include classes of cytochromes designated a, b, and c. Iron at the center of cytochromes accept and donates single electron 2+ 3+ - Cytochrone Fe Cytochrome – Fe + e (reduced) (Oxidized) Cytochrome with relatively less positive reduction potential (i. The free energy released is captured at three sites to pump protons against concentration gradient from matrix to inter membrane space generating proton gradient across inner mitochondrial membrane. As a result of this pH gradient is also formed, more positive (acidic) on the outer side more negative (basic) on the inner side of mitochondria. The simplest naturally occurring lipids are triacylglycerols formed by esterification of fatty acids with glycerol. In a different way the position of the double bond(s) can be indicated as shown in the second expression without the delta.

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