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If both substitution of one base for another in the DNA sequence of nucleotides (a point alleles of a gene are identical cheap cialis black 800mg free shipping impotence in men, the individual is mutation) purchase cialis black 800 mg without a prescription erectile dysfunction drugs insurance coverage, from deletion or insertions of bases into DNA, or from larger changes homozygous for this gene; if the alleles are (see Chap. For many alleles, the variation has a distinct phenotypic conse- different, he is heterozygous for this gene. Will quence that contributes to our individual characteristics, produces an obvious Sichel has two identical alleles for the sickle variant of the -globin gene that results in dysfunction (a congenital or genetically inherited disease), or increases suscep- substitution of a valine for a glutamate residue tibility to certain diseases. A defective protein may differ from the most common at the sixth position of the -globin chain. He allele by as little as a single amino acid that is a nonconservative substitution is, therefore, homozygous and has sickle cell (replacement of one amino acid with another of a different polarity or very dif- anemia. Individuals with one normal gene and ferent size) in an invariant region. Such mutations might affect the ability of the one sickle cell allele are heterozygous. They protein to carry out its function, catalyze a particular reaction, reach the appro- are carriers of the disease and have sickle cell priate site in a cell, or be degraded. Variants of an allele that occur with a significant frequency in the population are referred to as polymorphisms. Thus far in studies of the human genome, almost one third of the genetic loci appear to be polymorphic. When a particular variation of an allele, or polymorphism, increases in the general population to a frequency of over Will Sichel’s hemoglobin, HbS, comprises two normal chains and 2 -globin chains with the sickle cell variant ( S). The 2 2 change in amino acid composition from a glutamate to a valine in the chain allows sickle hemoglobin to be separated from normal adult hemoglobin (HbA, or ( A)) by electrophoresis. In electrophoresis, an aliquot of blood or other solution contain- 2 2 ing proteins is applied to a support, such as paper or a gel. When an electrical field is applied, proteins migrate a distance toward the anode (negative pole) or cathode (positive pole) that reflects small differences in their net charge. Electrophoresis of Will Sichel’s blood shows that he is homozygous for the sickle cell variant, HbS, and has increased amounts of fetal hemoglobin, HbF. Individuals with sickle cell trait are heterozygous and have both HbA and HbS, plus small amounts of HbF ( 2 2). In heterozygous individuals with sickle cell trait, the sickle cell allele provides some protection against malaria. Malaria is caused by the parasite Plasmodium fulciparum, which spends part of its life cycle in red blood cells. The infected red blood cells of individuals with normal hemoglobin (HbA) develop protrusions that attach to the lining of capillaries. This attachment occludes the vessels and prevents oxygen from reaching cells in the affected region, resulting in cell death. In heterozygous individuals, HbS in infected cells aggregates into long fibers that cause the cell to become distorted. These distorted cells containing the parasite are preferentially recognized by the spleen and are rapidly destroyed, thus ending the life of the parasite. In Will Sichel and other homozygous individuals with sickle cell anemia, the red blood cells sickle more frequently, especially under conditions of low oxygen tension (see Chapter 7). The result is a vaso-occlusive crisis in which the sickled cells clog capillaries and pre- vent oxygen from reaching cells (ischemia), thereby causing pain. The enhanced destruction of the sickled cells by the spleen results in anemia. Consequently, the sickle cell allele is of little advantage to homozygous individuals. Because heterozygous individuals occur more frequently in a population than homozygous individuals, a selective advantage in a het- erozygous state can outweigh a disadvantage in a homozygous state, causing the mutation to become a stable polymorphism in a popu- lation. As a consequence, the frequency of sickle cell anemia in parts of equatorial Africa in which malaria was endemic in the past is 1 in 25 births. Migration from Africa accounts for the high frequency of sickle cell anemia among blacks in the United States, which is approx- imately 1/400 at birth.

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In addition to Fe2 cheap 800mg cialis black amex erectile dysfunction nutritional treatment,Cu and to dissolved O2 best 800 mg cialis black erectile dysfunction videos, thereby forming superoxide. In contrast, when O2 binds to many other metals can also serve as single- cytochrome oxidase and accepts electrons, none of the O2 radical intermediates are electron donors in the Fenton reaction. CHAPTER 24 / OXYGEN TOXICITY AND FREE RADICAL INJURY 443 With insufficient oxygen, Cora Nari’s ischemic heart muscle mitochondria + NADH NAD were unable to maintain cellular ATP levels, resulting in high intracellular Na and Ca2 levels. The reduced state of the electron carriers in the absence of oxygen, and loss of mitochondrial ion gradients or membrane integrity, leads to NADH dehydrogenase increased superoxide production once oxygen becomes available during reperfusion. FMN/Fe–S The damage can be self-perpetuating, especially if iron bound to components of the elec- tron transport chain becomes available for the Fenton reaction, or the mitochondrial per- meability transition is activated. OXIDASES, OXYGENASES, AND PEROXIDASES Cytochrome Most of the oxidases, peroxidases, and oxygenases in the cell bind O2 and transfer b–c1, Fe-H single electrons to it via a metal. Free radical intermediates of these reactions may be accidentally released before the reduction is complete. Fe-H c Cytochrome P450 enzymes are a major source of free radicals “leaked” from reactions. O2 Fe-H–Cu Because these enzymes catalyze reactions in which single electrons are trans- Cytochrome H O aa3 ferred to O2 and an organic substrate, the possibility of accidentally generating 2 and releasing free radical intermediates is high (see Chapters 19 and 25). Induc- tion of P450 enzymes by alcohol, drugs, or chemical toxicants leads to increased Fig 24. When substrates for cytochrome P450 enzymes are not present, the electron transport chain. In the process of transporting electrons to O2, some of the elec- its potential for destructive damage is diminished by repression of gene tran- trons escape when CoQH• accidentally inter- scription. Fe-H repre- Hydrogen peroxide and lipid peroxides are generated enzymatically as major sents the Fe-heme center of the cytochromes. For example, monoamine oxidase, which oxidatively degrades the neurotransmitter dopamine, generates H2O2 at the mitochondrial mem- Carbon tetrachloride (CCl4), which is brane of certain neurons. Peroxisomal fatty acid oxidase generates H2O2 rather than used as a solvent in the dry-cleaning FAD(2H) during the oxidation of very-long-chain fatty acids (see Chapter 23). Xan- industry, is converted by cytochrome P450 to a highly reactive free rad- thine oxidase, an enzyme of purine degradation that can reduce O2 to O2 or H2O2 in the cytosol, is thought to be a major contributor to ischemia–reperfusion injury, ical that has caused hepatocellular necrosis in workers. When the enzyme-bound CCl4 especially in intestinal mucosal and endothelial cells. Lipid peroxides are also accepts an electron, it dissociates into CCl3· formed enzymatically as intermediates in the pathways for synthesis of many and Cl·. The CCl3· radical, which cannot con- eicosanoids, including leukotrienes and prostaglandins. IONIZING RADIATION polyunsaturated lipids of the endoplasmic Cosmic rays that continuously bombard the earth, radioactive chemicals, and x- reticulum. These reactions spread into the rays are forms of ionizing radiation. Ionizing radiation has a high enough energy plasma membrane and to proteins, eventually level that it can split water into the hydroxyl and hydrogen radicals, thus leading resulting in cell swelling, accumulation of to radiation damage to the skin, mutations, cancer, and cell death (Fig. Monoamine oxidase is a copper- Production of ROS by xanthine oxidase in endothelial cells may be enhanced containing enzyme that inactivates dopamine during ischemia–reperfusion in Cora Nari’s heart. In undamaged tissues, xan- in neurons, producing H2O2. The drug was thine oxidase exists as a dehydrogenase that uses NAD rather than O as an originally administered to inhibit dopamine 2 electron acceptor in the pathway for degradation of purines (hypoxanthine 4 xanthine degradation. However, current theory sug- 4 uric acid (see Chapter 41). When O2 levels decrease, phosphorylation of ADP to ATP gests that the effectiveness of the drug is also decreases, and degradation of ADP and adenine through xanthine oxidase increases. In related to decrease of free radical formation the process, xanthine dehydrogenase is converted to an oxidase. As long as O2 levels are within the cells of the basal ganglia. The below the high Km of the enzyme for O2, little damage is done.

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Shingosine is derived from serine and a specific fatty acid purchase 800 mg cialis black free shipping erectile dysfunction drugs at walgreens, palmitate buy cialis black 800 mg with visa impotence sentence. Ceramides are amides formed from sphingosine by attaching a fatty acid to the O O O CH2 R1 O CH2 R1 R2 C O CH O CH R2 C O CH O + 3 CH CH N CH CH O– 2 2 2 3 2 – CH3 – O O Choline Phosphatidylcholine Phosphatidic acid Fig. Phospholipids found in membranes, such as phosphatidylcholine, have a polar group attached to the phosphate. CHAPTER 5 / STRUCTURES OF THE MAJOR COMPOUNDS OF THE BODY 65 Phosphorylcholine Palmitoleic acid is an 7 fatty acid. It has one double bond between O CH + 3 the 9th and 10th carbons. It has 16 Ceramide OCH2 CH2 N CH3 carbons, like palmitic acid, so the double – CH3 bond must be at the 7th carbon from the O end. Sphingomyelin Galactose Ceramide Gal Galactocerebroside Oligosaccharide Ceramide Glc Gal GalNAc NANA Ganglioside Site of added sugar CH2OH H NH H OH C O CH (CH2)n CH CH3 (CH2)12 CH3 Ceramide Fig. The structure of ceramide is shown at the bottom of the figure. The portion of ceramide shown in blue is sphingosine. Different groups are added to the hydroxyl group of ceramide to form sphingomyelin, galactocerebrosides, and gangliosides. NANA N-acetylneuraminic acid, also called sialic acid; Glc glucose; Gal galactose; GalNAc N-acetylgalac- tosamine. Various sphingolipids are then formed by attaching different groups to the hydroxyl group on ceramide. As reflected in the names for cerebrosides and gangliosides, these sphingolipids contain sugars attached to the hydroxyl group of ceramide through glycosidic bonds. They are glycolipids (more specifically, gly- cosphingolipids). Sphingomyelin, which contains a phophorylcholine group attached to ceramide, is a component of cell membranes and the myelin sheath around neurons. Steroids Steroids contain a four-ring structure called the steroid nucleus (Fig. Choles- terol is the steroid precursor in human cells from which all of the steroid hormones are synthesized by modifications to the ring or C20 side chain. Although cholesterol is not very water soluble, it is converted to amphipathic water-soluble bile salts such as cholic acid. Bile salts line the surfaces of lipid droplets called micelles in the lumen of the intestine, where they keep the droplets emulsified in the aqueous environment. Cholesterol is one of the compounds synthesized in the human from branched 5- carbon units with one double bond called an isoprenyl unit (see Fig. Isoprenyl 66 SECTION TWO / CHEMICAL AND BIOLOGICAL FOUNDATIONS OF BIOCHEMISTRY 21 22 24 26 CH3 CH2 CH2 CH3 20CH 23CH2 25CH CH3 – CH3 27 COO 18 12 17 HO OH 11 13 16 C 19CH3 14 15 1 9 2 10 8 A 3 7 4 6 HO HO HO OH Cholesterol Cholic acid 17β–Estradiol Fig. The bile salt, cholic acid, and the steroid hormone 17 -estradiol are derived from cholesterol and contain the steroid ring structure. What structural features account units are combined in long chains to form other structures, such as the side chains of for the differences in the solubility coenzyme Q in humans and vitamin A in plants. NITROGEN-CONTAINING COMPOUNDS Nitrogen, as described in Section IB2, is an electronegative atom with two unshared electrons in its outer valence shell. At neutral pH, the nitrogen in amino groups is usually bonded to four other atoms and carries a positive charge. However, the pres- ence of nitrogen atom in an organic compound will increase its solubility in water, whether the nitrogen is charged or uncharged. Amino Acids Amino acids are compounds that contain an amino group and a carboxylic acid group. In proteins, the amino acids are always L- amino acids (the amino group is attached Although D-amino acids are not to the carbon in the L-configuration) (Fig. These same amino acids also serve usually incorporated into proteins as precursors of nitrogen-containing compounds in the body, such as phosphatidyl- in living organisms, they serve choline (see Fig. How- many other functions in bacteria, such as ever, our metabolic reactions occasionally produce an amino acid that has a or synthesis of cross-links in cell walls.

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This deformity is a very cosmetically objectionable posture effective 800mg cialis black icd 9 code for erectile dysfunction due to medication, espe- cially for adolescent and young adult females 800mg cialis black visa erectile dysfunction among young adults, to be lying in the hyperab- ducted hip-flexed position every time they are not sitting in their wheelchairs. Some of the children and many caretakers are bothered by this posture. Although it seems that this posture is a precursor to the type II anterior hip dislocation, no good documentation exists to suggest that it leads directly to anterior hip dislocation or inferior hip dislocation. This evolution of defor- mity may occur, but is so rare that it is not recognized as part of the precur- sor posture. A much more common bony deformity that occurs from this position as children grow, and especially as they go into adolescence, is the development of protrusio acetabuli from too much direct medial pressure. This is exactly opposite of what is seen when the widened teardrop with an- terior or posterosuperior dislocations are present. This acetabular protrusio may lead to degenerative arthritis in some young adults. Protrusio acetabuli may also leave children who are osteoporotic at risk for getting an acetabular fracture (Case 10. Treatment Treatment of the hyperabducted hip deformity can be divided into those with mild deformity and those with more severe deformity. Mild deformities are defined as hips having a passive adduction so they can be brought to neutral 10. Her mother, however, was not bothered by the and spastic quadriplegia, was seen for routine follow-up appearance. Physical examination showed the hips with and was noted to have severe hip abduction contractures. Radiographs of the hips showed that she mother did not feel she had any pain. The school care had acetabular protrusio (Figure C10. She sat well providers felt the hyperabduction deformity was very cos- in her wheelchair, which was extra wide and fitted with metically objectionable because she was always in this bilateral hip guides. At this time, her mother wished no position except when restrained in her wheelchair (Figure treatment. In children with open growth plates, muscle lengthening should be the primary procedure. However, the muscle lengthening will probably not work if there is a substantial acetabular pro- trusio already present. The muscle lengthening should involve a myotomy of the posterior gluteus medius just above the greater trochanter, sectioning the 596 Cerebral Palsy Management gluteus maximus just proximal to its insertion on the femur until more than 90° of hip flexion is possible. In general, all the short external rotators in- cluding the piriformis and gemellus should also be released, and sometimes an incision in the posterior capsule is needed if it is contracted and preventing internal rotation. In most children, this treatment needs to be combined with addressing the severe hamstring contracture, which can be accomplished by proximal hamstring lengthening through the lateral incision. This procedure is somewhat more difficult than doing it through the medial approach be- cause the sciatic nerve is more in the direct approach to the muscles. Postoperative Management After muscle lengthening, focus needs to be on gaining range of motion, es- pecially adduction and flexion, as well as keeping children positioned in hip flexion and adduction. Children’s primary seating chairs need to have at least an 80° back-to-seat angle so that they will be sitting with more than 90° of hip flexion. There is an initial tendency for this position to be somewhat uncomfortable for these children, and parents and therapists also want to position the children with a seatback angle at 110° or 120°, but this just fos- ters recurrence of the hip extension and abduction contracture. Parents are also encouraged to have children side lying during sleep. The most common problem after this muscle lengthening is recurrence of the contracture, and postoperative monitoring should focus primarily on this recurrence. For the moderately or more severely involved abduction contracture defined as those with less than 45° of hip flexion and less than 0° of hip ad- duction, a varus shortening osteotomy to reposition the lower extremity should be included in the treatment. This osteotomy should be the primary procedure for adolescents who have neared skeletal maturity and for chil- dren who have had protrusio acetabuli. Again, the rehabilitation following this procedure should focus on getting children back up into the wheelchair quickly, working on range of motion to maintain the adducted position, and working on hip flexion. These are the primary postures that need to be cor- rected to have good sitting posture.

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