By H. Ateras. Aspen University. 2018.
Two forms of the virus have been discovered cheap 100mg kamagra oral jelly amex erectile dysfunction causes and treatment, HIV- error rate because it does not have 1 best kamagra oral jelly 100 mg impotence beta blockers, which is prevalent in industrialized countries, and HIV-2, which is prevalent in proofreading capability. Eight to ten years or more can elapse between the initial tion of mismatched bases leads to evolution infection and development of the full-blown syndrome. Subsequently, con- Mutations in the viral reverse transcriptase formational changes occur that allow the viral coat proteins to bind to a chemokine gene cause the enzyme to become resistant coreceptor in the cell membrane. The lipid in the viral coat then fuses with the cell to drugs such as ZDV. Current vaccines membrane, and the viral core enters the cell, releasing its RNA and enzymes developed experimentally against the gp120 (including the reverse transcriptase) by a process called “uncoating. As a consequence scriptase uses the viral RNA as a template to produce a single-stranded DNA copy, of the rapid mutation rate of HIV, current which then serves as a template for synthesis of a double-stranded DNA. An inte- treatments for AIDS have limited effective- grase enzyme, also carried by the virus, enables this DNA to integrate into the host ness, and a cure has proved elusive. CHAPTER 14 / TRANSCRIPTION: SYNTHESIS OF RNA 255 HIV Chemokine coreceptors CD4 Fusion of virus with cell membrane receptors Uncoating Viral RNA Reverse transcriptase Reverse transcriptase synthesizes DNA Double-stranded DNA Viral DNA integrates into host cell DNA + Transcription Tat + Rev Unspliced Spliced RNA RNA Translation Rev, Nef, Tat Env Gag, Pol polyprotein Nef protease + Env (glycoproteins gp 41 and 120) Mature virus Fig. The HIV virus particle binds to the CD4 recep- tor and a chemokine coreceptor in the host cell membrane. The virus enters the cell and uncoats, releasing its RNA and proteins. The viral enzyme reverse transcriptase produces a double-stranded DNA copy that is integrated into the host cell genome. Transcripts of the viral DNA are spliced and translated to produce the proteins Tat, Rev, and Nef. Tat stimulates transcription of the viral DNA, and Rev causes the viral RNA transcripts to leave the nucleus unspliced. The unspliced RNA serves as the viral genome and also codes for the proteins of the viral core and envelope. The envelope proteins (gp41 and gp120, which are derived from the env protein) enter the cell membrane. The viral core pro- teins are synthesized as a polyprotein, which is cleaved by a protease as the viral particles form and bud from the cell membrane. The particles carry membrane lipid as a coat that con- tains gp41 and gp120. Nef indirectly aids in the assembly of viral particles. Pol is the reverse transcriptase produced from the viral RNA. As Rev accumulates, it allows unspliced viral RNA to leave the nucleus and to produce proteins of the viral envelope and viral core, including reverse tran- scriptase. Two of the envelope glycoproteins (gp41 and gp120, which are derived from the env gene product) form a complex that embeds in the cell membrane. The other proteins, which are translated as a polyprotein and cleaved by the viral pro- tease, combine with the full-length viral RNA to form core viral particles, which bud from the cell membrane. Thus, the virus obtains its lipid coat from the host cell membrane, and the coat contains the viral proteins gp41 and gp120. These surface proteins of the virus bind to CD4 receptors on other human helper T lymphocytes, and the infection spreads. In an uninfected person, helper T lymphocytes usually number approximately 1,000/mL. Infection with HIV causes the number of these cells to decrease, which results in a deficiency of the immune system. When the number of T lymphocytes drops below 200/mL, the disease is in an advanced stage, and opportunistic infec- tions, such as tuberculosis, occur. Although macrophages and dendritic cells lack CD4 receptors, they can also become infected with HIV and can carry the virus to the central nervous system. Drugs currently used to treat AIDS The most effective means of combating HIV infection involves the use of drugs act on the viral reverse transcrip- that inhibit the viral reverse transcriptase or the viral protease. A more complete coverage of transcription can be found in: The protease inhibitors (e. Oxford: Oxford University Press, to the protease and prevent it from cleaving 2000:232–272. References covering diseases discussed in this chapter: Clumeck N. Choosing the best initial therapy for HIV-1 infection. The Metabolic and Molecular Bases of Inherited Disease.
Acetaldehyde may be produced faster than it can be metab- rises above 18 mM (the legal intox- olized by acetaldehyde dehydrogenases cheap kamagra oral jelly 100 mg mastercard erectile dysfunction from alcohol, thereby increasing the risk of hepatic injury order 100mg kamagra oral jelly with visa erectile dysfunction treatment with fruits. In addition, cytochrome P450 enzymes are capable of generating free radicals, and central nervous system are affected. Induction of CYP2E1 increases the rate of ethanol clearance from the blood, thereby E. Variations in the Pattern of Ethanol Metabolism contributing to increased alcohol tolerance. However, the apparent ability of a chronic The routes and rates of ethanol oxidation vary from individual to individual. Dif- alcoholic to drink without appearing inebri- ferences in ethanol metabolism may influence whether an individual becomes a ated is partly a learned behavior. Factors that determine the rate and route of ethanol oxidation in individuals include: • Genotype—Polymorphic forms of alcohol dehydrogenases and acetaldehyde dehydrogenases can greatly affect the rate of ethanol oxidation and the accumu- lation of acetaldehyde. CYP2E1 activity may vary as much as 20-fold between individuals, partly because of differences in the inducibility of different allelic variants. After chronic consumption of ethanol, gastric ADH decreases in both men and women, but the gender differences become even greater. Gender differ- ences in blood alcohol levels also occur because women are normally smaller. Furthermore, in females, alcohol is distributed in a 12% smaller water space because a woman’s body composition consists of more fat and less water than that of a man. Small amounts of ethanol are metabo- lized most efficiently through the low Km pathway of class I ADH and class II ALDH. Little accumulation of NADH occurs to inhibit ethanol metabolism via these dehydrogenases. However, when higher amounts of ethanol are consumed in a short period, a disproportionately greater amount is metabolized through MEOS. MEOS, which has a much higher Km for ethanol, functions principally at high concentrations of ethanol. A higher activity of MEOS would be expected to correlate with tendency to develop alcohol-induced liver disease, because both acetaldehyde and free radical levels would be increased. The Energy Yield of Ethanol Oxidation The ATP yield from ethanol oxidation to acetate varies with the route of ethanol metabolism. If ethanol is oxidized by the major route of cytosolic ADH and mito- chondrial ALDH, one cytosolic and one mitochondrial NADH are generated with a maximum yield of 5 ATP. Oxidation of acetyl CoA in the TCA cycle and electron transport chain leads to the generation of 10 high-energy phosphate bonds. How- ever, activation of acetate to acetyl CoA requires two high-energy phosphate bonds (one in the cleavage of ATP to AMP pyrophosphate and one in the cleavage of pyrophosphate to phosphate), which must be subtracted. Thus the maximum total energy yield is 13 moles of ATP per mole of ethanol. In contrast, oxidation of ethanol to acetaldehyde by CYP2E1 consumes energy in the form of NADPH, which is equivalent to 2. Thus, for every mole of 464 SECTION FOUR / FUEL OXIDATION AND THE GENERATION OF ATP At Ivan Applebod’s low level of ethanol metabolized by this route, only a maximum of 8. The overall energy yield of 13 ATP per ethanol molecule II. TOXIC EFFECTS OF ETHANOL METABOLISM accounts for the caloric value of ethanol, approximately 7 Cal/g. However, chronic Alcohol-induced liver disease, a common and sometimes fatal consequence of consumption of substantial amounts of alco- chronic ethanol abuse, may manifest itself in three forms: fatty liver, alcohol-induced hol does not have the effect on body weight hepatitis, and cirrhosis. Each may occur alone, or they may be present in any combi- expected from the caloric intake. Alcohol-induced cirrhosis is discovered in up to 9% of all partly attributable to induction of MEOS, autopsies performed in the United States, with a peak incidence in patients 40 to 55 resulting in a proportionately greater metab- years of age. In general, weight loss diets recom- ing to a fatty liver. It also can result in ketoacidosis or lactic acidosis and cause mend no, or low, alcohol consumption hypoglycemia or hyperglycemia, depending on the dietary state. These effects are because ethanol calories are “empty” in the considered reversible. Diffuse damage to hepatocytes results in cirrho- sis, characterized by fibrosis (scarring), disturbance of the normal architecture and blood flow, loss of liver function and, ultimately, hepatic failure. Acute Effects of Ethanol Arising from the Increased NADH /NAD Ratio Many of the acute effects of ethanol ingestion arise from the increased NADH/NAD ratio in the liver (Fig. At lower levels of ethanol intake, the rate of ethanol oxidation is regulated by the supply of ethanol (usually determined by how much ethanol we consume) and the rate at which NADH is reoxidized in the electron transport chain. NADH is not a very effective product inhibitor of ADH or ALDH, and there is no other feedback regulation by ATP, ADP, or AMP. As a con- sequence, NADH generated in the cytosol and mitochondria tends to accumulate, increasing the NADH/NAD ratio to high levels (see Fig.
The fact that there is no time loss in training or competitive participation does not necessarily mean a non-significant injury purchase kamagra oral jelly 100 mg with mastercard causes of erectile dysfunction and premature ejaculation. An athlete will play because he/she is eager to keep his/her place (if it is a team sport) and also because it is their job and they are paid to do it (in a professional sport) trusted kamagra oral jelly 100 mg erectile dysfunction pills over the counter. In sports medicine we are thus all epidemiologists “concerned with quantifying injury occurrence with respect to who is affected by injury, where and when injuries occur and what is their outcome – for the purposes of explaining why and how injuries occur and identifying strategies to control and prevent them”. With the advent of electronic literature searches and the access to numerous statistical packages that exist today this is indeed a distressing finding. To interpret the literature, the researcher must be able to discern good studies from bad, to verify whether conclusions of a particular study are valid, and to understand the limitations of a study. Seek advice from experts such as epidemiologists or statisticians before the data collection is begun, it is too late afterwards! A study should ideally have a research question/hypothesis or identify a problem to be Box 2. Next, identify the risk factors that are felt to have appropriate influence on the question/problem, followed by the planning of the intervention and subsequent evaluation of the outcome. Why are certain treatments/ interventions used if they have never been proven to be effective? Current problems in sports injury data collection exist today because many studies are limited by the fact that the data collection is from the injured athletes alone (case series) or of risk factors alone, which do not allow the use of the epidemiological concept of “athletes being at risk”. Randomisation is difficult but must be worked towards as it is a key concept. Case series studies are not helpful in injury prevention but if they are to be used then confounding variables, such as previous injuries, must be addressed. Many clinicians, in a position to access data, are not sufficiently trained in study design and statistical analysis to collect the required information or put it into a format for publication. Therefore there is much information in existence that, frustratingly, is not published and cannot be accessed. This is an issue that, if addressed, will take sports epidemiology further. Partnerships can be made with medical students and public health schools to alleviate this problem. Currently there is no common operational definition of sports injuries in existence, which constitutes one of the biggest problems in sports injury data collection. What constitutes an injury in some sports may not be what is considered an injury in another sport. Some studies define an injury as “an incident requiring medical attention following a sport related activity (typical to that sport)”1, 5–7 others only define it as an injury “if it requires the athlete to miss the rest of that session or a subsequent training or participation session”. These guidelines can be a set definition of what constitutes an injury, with a sub-division of definitions (codes) expansive enough to incorporate all sporting diagnoses and subcategories for specific injury definitions, which can be supplemented for some of the atypical sports. Furthermore, there is no set definition of severity. Some studies classify severe injuries as those “requiring five weeks out of competitive competition” others classify severe injuries as those “requiring five games to be missed”. For example, if a team-player missed three games with an ankle sprain and another team-player (examined by the same physician) missed five games, but both injuries were considered to be 14 Methodology in research exactly the same grade and had the exact same rehabilitation, would the conclusion be that one ankle sprain was wrongly diagnosed initially or wrongly rehabilitated? However, consider the fact that both the injuries were exactly the same and the second team-player missed more games simply due to the fact that his team had two additional midweek fixtures as well as the regular weekend game. Dependent on the definition of injury if the classification of severe is five or more games missed one sprain is severe and the other is moderate, even though these injuries are the same. When collecting and reporting on data these considerations have to be taken into account. They can be controlled by collecting data in two ways, by total games/competition days missed and total days/weeks missed with both reported in the results. Currently there is no set format for data collection across sports. Largely this is due to the fact that there are no set definitions of diagnoses and severity. If these were to be defined then an inclusion criteria of data variables for universal collection could also be set. This would help solve some of the problems of the data collections that exist. The criteria would be standardised allowing comparisons like for like, whilst also allowing clinicians or scientists to collect in a variety of formats as long as the criteria were adhered to. These formats could initially be paper or electronic, although undoubtedly the way forward is electronic databases. An additional problem is that the sizes of the samples vary. Some studies into team sports refer to only one team, others use multiple teams. For example, if a paper comparing two different types of team sports reported that at the same stadium, on the same day, the first team sport had 12 injuries and second team sport had only 10 injuries and concluded the first sport was more dangerous than the second, the conclusion would not be acceptable unless the authors had also shown “how long each sport was played for” i. Also the reader should be told “how many players were playing in each team of the different sports.
When the distal 25% of the wound was opened purchase kamagra oral jelly 100 mg with visa erectile dysfunction drugs generic, it covers most of the hardware (Figure C9 buy generic kamagra oral jelly 100 mg line erectile dysfunction doctor houston. No purulent material could be expressed from ure C9. He did not have a fever for 3 weeks and the the proximal end of the wound. A the remaining 10 days of intravenous antibiotic and to central line was inserted in expectation of needing long- continue the wet-to-dry cover dressing. Jordan returned term antibiotic and he was started on cephazolin. The fol- 6 weeks after drainage, and the central line was removed lowing day the dressing was changed on the ward under and he was switched to oral trimethoprin sulfamethoxi- sedation, and dressing changes were started three times a zole twice a day. The culture grew Staphylococcus aureus, and he was was still open, 15 cm in length and 4 cm wide. After 10 days, the wound weeks after this, he was seen in the outpatient clinic with had less purulent material and was getting drier, so the the wound completely healed. The antibiotic was de- dressings were changed to saline-soaked packing. After 2 creased to once a day, and his mother was informed that more weeks, then 3. Radiographs was developing excellent granulation tissue and the pack- showed good healing and formation of fusion mass 4 ing was discontinued in favor of a loose wet-to-dry cover months after the original fusion. After 3 to 4 weeks healthy granulation tissue Figure C9. Spine 495 wound is very large, another return to the operating room for dressing change and debridement under general anesthesia may be required. The debridement may continue on the ward as the necrotic tissue separates and is then re- moved. After all the necrotic tissue has been removed, the wound is allowed to close by secondary intention from the bottom up. The packing should be very loose with a saline-soaked sponge; however, it should be clear that the granulation tissue closes over the rod and that it does not close leaving a fluid-filled cavity as the skin closes over the top. Managing this closure re- quires that physicians continue to check the wound every day or two. This need for frequent wound checks and intravenous antibiotics means that these patients are kept in the hospital for 4 to 5 weeks of treatment until granu- lation tissue has covered the rod, which is the criteria for discharge to out- patient and home nursing care. Typically, intravenous antibiotics specific to the results of the culture are continued at full doses for 6 weeks. After 6 weeks, children are kept on antibiotic suppression therapy with one antibiotic orally if a simple antibiotic is available against the specific organism. This sup- pression therapy is continued for 6 to 12 months. Except for one patient with a very severe infection of the whole spine combined with meningitis, all our other deep wound infections have cleared and the hardware has remained covered and in place without evidence of any late infections. We have had two late deep wound infec- tions occurring 2 and 5 years after the original surgery. One of these was directly related to a concurrent urinary tract infection; however, the other was a staphylococcus infection that was not directly related to any known concurrent problem. Both these infections involved the whole spinal rod and required removal of the rod and all wires. Both wounds healed, and one child has done well for 6 years ex- cept the fusion mass has bent, so he now has an additional 20° of scoliosis (Case 9. The other boy healed his wound well and had almost closed the deep wound when he had a sudden period of shortness of breath followed by a cardiac arrest at home. We have never seen a case of late sterile drainage requiring removal of the hardware, which has been reported with other systems. Usually, there should be a very specific goal to be accomplished, such as getting children into better sitting positions, treating painful nonunions, or improving respi- ratory function. Based on a well-defined problem, a careful plan to achieve these specific goals should be outlined. Using this proximal end avoids having to remove all the old instrumentation and provides a source for rigid proximal fixation. The apex of the curve must be identified, and 496 Cerebral Palsy Management Case 9. With dressing changes and plegic CP was 5 years after a successful posterior spinal antibiotic, the infection cleared.
A stimulus is any force that can start an action po- tential by opening membrane channels Neurotransmitter and allowing Na to enter the cell discount 100 mg kamagra oral jelly overnight delivery erectile dysfunction causes lower back pain. A molecules Presynaptic The Role of Myelin in Conduc- membrane tion As previously noted discount kamagra oral jelly 100mg free shipping smoking and erectile dysfunction statistics, some axons are coated with the fatty material Vesicle myelin. If a fiber is not myelinated, the action potential spreads continuously Neurotransmitter along the membrane of the cell (see Fig. When myelin is present on an axon, however, it insulates the fiber Synaptic cleft against the spread of current. This would appear to slow or stop conduc- Postsynaptic Receptor tion along these fibers, but in fact, the membrane myelin sheath speeds conduction. The B reason is that the action potential must “jump” like a spark from node (space) Figure 9-9 A synapse. As described in Chapter 8, information must be Dendrite passed from one cell to another at the synapse across a Axon tiny gap between the cells, the synaptic cleft. Information usually crosses this gap in the form of a chemical known as a neurotransmitter. While the cells at a synapse are at rest, the neurotransmitter is stored in many small vesicles (bubbles) within the enlarged endings of the axons, usu- ally called end-bulbs or terminal knobs, but known by sev- eral other names as well. Cell body When a nerve impulse traveling along a neuron mem- brane reaches the end of the presynaptic axon, some of these vesicles fuse with the membrane and release their neurotransmitter into the synaptic cleft (an example of ex- ocytosis, as described in Chapter 3). The neurotransmitter then acts as a chemical signal to the postsynaptic cell. Axon end-bulbs from other On the postsynaptic receiving membrane, usually that neurons of a dendrite, but sometimes another part of the cell, there are special sites, or receptors, ready to pick up and respond to specific neurotransmitters. Receptors in the Axons from postsynaptic cell membrane influence how or if that cell other neurons will respond to a given neurotransmitter. Figure 9-10 The effects of neurotransmitters on a neuron. A single neuron is stimulated by axons of many other neurons. Neurotransmitters Although there are many known The cell responds according to the total of all the excitatory and neurotransmitters, the main ones are epinephrine (ep-ih- inhibitory neurotransmitters it receives. NEF-rin), also called adrenaline; a related compound, norep- inephrine (nor-ep-ih-NEF-rin), or noradrenaline; and acetyl- choline (as-e-til-KO-lene). Acetylcholine (ACh) is the Electrical Synapses Not all synapses are chemically neurotransmitter released at the neuromuscular junction, the controlled. In smooth muscle, cardiac muscle, and also in synapse between a neuron and a muscle cell. All three of the the CNS there is a type of synapse in which electrical en- above neurotransmitters function in the ANS. It is common to ergy travels directly from one cell to another. The mem- think of neurotransmitters as stimulating the cells they reach; branes of the presynaptic and postsynaptic cells are close in fact, they have been described as such in this discussion. These electrical synapses allow more rapid synaptic cell and keep it from reacting, as will be demon- and more coordinated communication. In the heart, for strated later in discussions of the autonomic nervous system. One cell can branch to stimulate many receiving cells, or a single cell may be stimulated by a number of different axons (Fig. The cell’s response is based ◗ The Spinal Cord on the total effects of all the neurotransmitters it receives at any one time. The spinal cord is the link between the peripheral nerv- After its release into the synaptic cleft, the neuro- ous system and the brain. It also helps to coordinate im- transmitter may be removed by several methods: pulses within the CNS. The spinal cord is contained in and protected by the vertebrae, which fit together to form ◗ It may slowly diffuse away from the synapse. The column of bone again, a process known as Reuptake. This disparity in growth continues to increase, so that in Checkpoint 9-9 Chemicals are needed to carry information adults, the spinal cord ends in the region just below the across the synaptic cleft at a synapse. THE NERVOUS SYSTEM: THE SPINAL CORD AND SPINAL NERVES 187 Brain C1 C2 Cervical Brain stem C3 Spinal cord C4 plexus Cervical C5 Cervical nerves C6 (C1—8) C7 Brachial enlargement C8 plexus T1 Radial nerve T2 T3 Spinal T4 cord T5 Median nerve T6 Ulnar nerve T7 Thoracic T8 nerves Intercostal T9 nerves T10 9 (T1—12) T11 Phrenic nerve T12 Lumbar L1 enlargement L2 L3 Lumbar L4 Lumbosacral nerves L5 plexus (L1—5) Femoral nerve S1 Sacral S2 S3 nerves Sciatic nerve S4 (S1—5) S5 Coccygeal CO1 nerve A B Figure 9-11 Spinal cord and spinal nerves. ZOOMING IN Is the spinal cord the same length as the spinal column? How does the number of cervical vertebrae compare with the number of cervical spinal nerves? Structure of the Spinal Cord commissure (KOM-ih-shure). In the center of the gray commissure is a small channel, the central canal, that The spinal cord has a small, irregularly shaped internal contains cerebrospinal fluid, the liquid that circulates section of gray matter (unmyelinated tissue) surrounded around the brain and spinal cord.
8 of 10 - Review by H. Ateras
Votes: 223 votes
Total customer reviews: 223