By Z. Sanford. University of La Vernee.

They are also involved in the positioning of the Golgi complex and the movement of chromosomes during mitosis generic sildenafil 25mg. Microtubules consist of polymerized arrays of and tubulin dimers that form A variety of human cells have cilia 13 protofilaments organized around a hollow core (see Fig discount sildenafil 100 mg amex. Three different and flagella, hairlike projections tubulin polypeptides ( , , and ) of similar amino acid composition are encoded from the surface that have a stroke- like motion. These projections contain a flex- by related genes; and dimers polymerize to form most microtubules, and - ible organized array of microtubules. Tubulin dimers composed of one and or mucus is propelled over the surface of cil- one subunit bind GTP, which creates a conformational change in the dimer that iated epithelial cells by the coordinated beat- favors addition of dimers to the tubulin polymer. A sperm cell swims by means of ciate from both ends of the tubulin, but the end to which they add more rapidly (the a flagellum. As GTP is hydrolyzed to GDP, the binding of tubu- lin subunits is weakened, resulting in their dissociation (dynamic instability). Thus, the net rate and direction of growth is dictated by the fastest growing end of the microtubule. Actin Filaments Colchicine has a narrow therapeu- tic index (i. The actin polymer, called F-actin, is amount that produces an adverse effect). Its composed of a helical arrangement of globular G-actin subunits (Fig. Fortunately, neutrophils concen- trate colchicine, so they are affected at lower A intakes than other cell types. Neutrophils Plus end lack the transport protein P-glycoprotein, a member of the ABC cassette family (which A A includes the CFTR channel). In most other A cell types, P-glycoprotein exports chemicals A such as colchicine, thus preventing their A accumulation. A A A Pi F-actin A A A A A A A A A Minus end A G-actin subunit Fig. The polymer F-actin is assembled from G-actin subunits con- taining bound ATP. The conformational change shifts the equilibrium so that dissociation of the G-actin subunits is favorable at the minus end of the polymer. Once dissociated, the actin subunits exchange ADP for ATP, which may again associate with the actin polymer. At the plus end of the molecule, association is favored over dissociation. New subunits of G-actin containing ATP continuously combine with the assembled F-actin polymer at the plus end. As F-actin elongates, bound ATP is hydrolyzed to ADP, so that most of the polymer contains G-actin-ADP subunits. The conformation of ADP-actin favors dissociation from the minus end of the polymer; thus, the polymer is capable of lengthening from the plus end. This directional growth can account for certain types of cell movement and shape changes: the formation of pseudopodia that surround other cells during phago- cytosis, the migration of cells in the developing embryo, or the movement of white blood cells through tissues. Actin polymers form the thin filaments (also called microfilaments) in the cell that are organized into compact ordered bundles or loose network arrays by cross- linking proteins. Short actin filaments bind to the cross-linking protein spectrin to form the cortical actin skeleton network (see Fig. In muscle cells, long actin filaments combine with thick filaments, composed of the protein myosin, to pro- duce muscle contraction. The assembly of G-actin subunits into polymers, bundling of fibers, and attachments of actin to spectrin and to the plasma membrane proteins and organelles, are mediated by a number of actin-binding proteins and G-proteins from the Rho family. Intermediate Filaments Intermediate filaments (IF) are composed of fibrous protein polymers that provide structural support to membranes of the cells and scaffolding for attachment of other cellular components. Each IF subunit is composed of a long rod-like -helical core containing globular spacing domains, and globular N- and C-terminal domains. The -helical segments of two subunits coil around each other to form a coiled coil, and then combine with another dimer coil to form a tetramer. Depending on the type of filament, the dimers may be either hetero- or homo-dimers. The tetramers join end- to end to form protofilaments and approximately eight proto filaments combine to form filaments (Fig. Filament assembly is partially controlled through phos- phorylation. In contrast to actin thin filaments, the 50 or so different types of intermediate fil- aments are each composed of a different protein having the same general structure described above (Table 10.

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The early treatment is to provide the children sup- port through the use of an orthotic buy 25mg sildenafil with visa, usually starting with a solid ankle AFO cheap sildenafil 50 mg online, then following with an articulated AFO for the second orthotic. If a child has a very spastic gastrocsoleus, botulinum toxin injection for two or three cycles can help parents apply the AFO and make AFO wear more comfortable for the child. Usually, by 4 to 7 years of age, the gastrocsoleus contracture has become so severe that brace wear is no longer possible. On physical exami- nation, children often demonstrate a contracture of both the gastrocnemius and soleus. The kinematic examination will show equinus throughout the gait cycle, and knee flexion at foot contact may be increased as children preposi- tion the knee to avoid high external extension moments from the ground re- action force during weight acceptance. Often, these children will be toe walk- ing on the unaffected side as well, and a careful assessment is required to make sure that this is compensatory toe walking and not mild spastic response in a limb that was erroneously thought to be normal. The physical examination and kinematic evaluation are most useful for this assessment. The unaffected ankle should have adequate dorsiflexion measuring 5° to 10° with knee ex- tension. The ankle moment should show normal late stance phase plantar flex- ion moment or a variable moment, one or two of which may look almost normal. The affected ankle will also be more consistently abnormal with high early plantar flexion moments. If children have been allowed to walk on the toes until late middle childhood, their unaffected ankles will often develop plantar flexion contractures from persistent toe walking. The physical ex- amination will show a reduced ankle range of motion, and the ankle moment will still show the same variability with much better power generation than the affected ankle. The step length of the affected side is usually longer and the stance phase time of the normal limb is longer. These changes occur be- cause the affected leg has a normal swing phase but is more unstable in stance phase. If the normal ankle is contracted it will need a gastrocnemius length- ening or the normal ankle will become a driving force toward toe walking after correction of the contracture on the primarily involved side (Case 7. Outcome of Tendon Lengthening The need for postoperative orthotic use varies, but braces are not routinely needed. If children do not gain foot flat at initial contact by 3 to 6 months after surgery, an AFO should be used, usually an AFO that allows dorsi- flexion to encourage the tibialis anterior to gain function. This AFO can be either an articulated AFO or a half-height wrap-around AFO with an anterior ankle strap. With appropriate early treatment, most children with type 2 hemiplegic pattern CP can be free of an orthosis by early grade school. Some children will develop an equinus contracture again in late childhood or ado- lescence. If an adolescent is willing to tolerate the orthosis, another round of Botox injections and orthotic wear can delay surgery until he is near the completion of growth. Approximately 25% of type 2 hemiplegics will need a second gastrocnemius or tendon Achilles lengthening in adolescence. Ado- lescents or young adults with type 2 hemiplegia should seldom need to wear an orthosis after this last lengthening. Long toe flexor spasticity may also be present, but this seldom needs surgical treatment. In early childhood, the feet are often in a planovalgus position; however, as children gain increased tone, gastrocnemius and soleus equinus develops. He then used articulating AFOs until he was 4 years old, when he complained that the orthotics caused him pain. After multiple attempts to make the orthotics comfortable, he was allowed to walk without orthotics for 1 year until age 5 years, when he had a full analysis. The physical examination demonstrated that he had popliteal angles of 35° bilaterally, and ankle dorsi- flexion on the right was only −25° with both knee flex- ion and extension. On the left, he had ankle dorsiflexion to 20° with knee flexion, but only 5° with knee extension. The observation of his gait showed that he was toe walk- ing bilaterally, although higher on the right than the left. It was recommended that he have an open Z-lengthening of the tendon Achilles. Postoperatively, he used an artic- ulated AFO for 1 year, and following this, he developed good active dorsiflexion with a plantigrade foot position (Figure C7. Children with type 2 hemiplegia develop planovalgus that needs treatment only on rare occasions.

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For children with open tri- radiate cartilage and some thickening of the medial wall or femoral head de- formity buy sildenafil 75 mg overnight delivery, reconstruction is still an option 50 mg sildenafil amex. This area is not very clearly defined and depends somewhat on the experience of the surgeon, the willingness of Case 10. The hip clearly appeared to be the source having severe pain. They reported that if she did not move of the pain, and the radiograph was consistent (Figure she would be quiet; however, any movement would cause C10. A reconstruction was performed with an ad- her to cry out. She was fed by ductor lengthening on the left and bilateral femoral varus gastrostomy tube, took medication to control seizures, and derotation shortening osteotomy with a peri-ilial pelvic had chronic constipation. She was mobilized immedi- On physical examination she had good head control but ately, and by 3 months all the preoperative pain had re- could not prop-sit, she did not weight bear, and had mild solved. She was sitting all day and not crying with dress- scoliosis. The left hip lacked 20° to come to neutral ab- ing and other position changes. The right hip abducted 70° but could not be 20 years, 11 years after reconstruction, the hips had sym- brought to the neutral adduction. The popliteal angle on metric range of motion with full extension and flexion, the left was 90° and on the right it was 60°. The feet were abduction to 20°, but rotation limited to 20° internally in severe planovalgus. On physical examination she cried and 30° externally (Figure C10. No hip pain was with attempted left hip abduction and all attempts to sit, present, and the hip appeared to have a nearly normal stand, or change her position. In general, younger children, between 6 and 12 years of age, who are having pain from a severely subluxated or dislocated hip can have the reconstructive treatment indications pushed harder because more remodeling capability remains (Case 10. Conversely, fully mature children with a sub- stantial triangular-shaped femoral head have very little possibility of getting a good result from reconstruction because of limited ability for remodeling. She had been sent as a second opinion from a physi- walking decreased related to both her increased size and cian who had recommended a proximal femoral resection. Her parents wanted to try to get her back to ambulating One year prior she had undergone a dorsal rhizotomy with a walker again and were very hesitant to have a re- because of increased hip pain. After an extensive discussion in which her parents she had never been able to stand. She had mild mental re- stated that they were willing to risk a second operation tardation, fed herself, and was very clear that her hip hurt if reconstruction failed, a reconstruction was performed. On physical examination she After the reconstruction, the hip subluxated inferiorly was noted to be somewhat overweight at 70 kg and was due to no muscle tone (Figure C10. However, imme- extremely hesitant about all aspects of the examination. By a 6-year follow-up at age 21 years, could not be obtained; however, the left lower extremity she had painless free motion of the hip except for very had no spasticity and no apparent contractures. She still could not stand hip caused pain with motion but also had no spasticity. First, it is important to correct the pathomechanics, which is the original eti- ology. The abnormal hip joint reactor force vector has to be corrected by ad- equate lengthening of the hip adductor muscles. The high-force environment that has caused this should be treated by adequate femoral shortening so that the hip joint is no longer under high force after reconstruction. The second major aspect of a reconstructive procedure is correction of the acetabular de- formity, which is of such severity that it will not be able to remodel and needs to be corrected directly. The third major aspect of a reconstruction is mak- ing all attempts to leave children with symmetric movement of the hips and symmetric limb lengths. The standard hip reconstruction involves open adductor lengthening, followed by a varus shortening derotational osteotomy of the femur and a reconstruction of the acetabulum using a peri-ilial acetabular osteotomy. The peri-ilial osteotomy and the Dega osteotomy are somewhat confusing, and the use of the Dega osteotomy for spastic hip disease was initially described as extending posteriorly into the sciatic notch. The San Diego osteotomy continues to use the anterior approach to the hip capsule rather than the medial approach, which is ad- vocated in the peri-ilial approach. Cast immobilization continues to be used after the pelvic osteotomy by some, as opposed to the immediate mobilization used after the peri-ilial osteotomy. However, outcomes of both procedures are very similar.

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FATE OF AMINO ACIDS IN THE FED STATE The amino acids derived from dietary proteins travel from the intestine to the liver in the hepatic portal vein (see Fig order 100 mg sildenafil. The liver uses amino acids for the synthesis of serum proteins as well as its own proteins order 50mg sildenafil, and for the biosynthesis of nitrogen-containing compounds that need amino acid presursors, such as the CHAPTER 2 / THE FED OR ABSORPTIVE STATE 27 nonessential amino acids, heme, hormones, neurotransmitters, and purine and pyrimidine bases (e. The liver also may oxidize the amino acids or convert them to glucose or ketone bodies and dispose of the nitrogen as the nontoxic compound urea. Many of the amino acids will go into the peripheral circulation, where they can be used by other tissues for protein synthesis and various biosynthetic pathways, or oxidized for energy (see Fig. Proteins undergo turnover; they are constantly being synthesized and degraded. The amino acids released by protein breakdown enter the same pool of free amino acids in the blood as the amino acids from the diet. This free amino acid pool in the blood can be used by all cells to pro- vide the right ratio of amino acids for protein synthesis or for biosynthesis of other compounds. In general, each individual biosynthetic pathway using an amino acid precursor is found in only a few tissues in the body. SUMMARY OF THE FED (ABSORPTIVE) STATE After a meal, the fuels that we eat are oxidized to meet our immediate energy needs. Excess glucose and other fuels are stored, as glycogen mainly in muscle and liver, and as triacylglycerols in adipose tissue. Amino acids from dietary proteins are converted to body proteins or oxidized as fuels. CLINICAL COMMENTS Ivan Applebod’s waist circumfer- Ivan Applebod. Applebod was advised that his obesity represents ence indicates he has the android a risk factor for future heart attacks and strokes. He was told that his body pattern of obesity (apple shape). This expanded blood volume not only contributes to his elevated blood pres- different patterns, android and gynecoid. This increased load will cause his heart muscle to thicken and eventually on their abdomens and upper body (an to fail. Applebod’s increasing adipose mass has also contributed to his development store fat around their breasts, hips, and of type 2 diabetes mellitus, characterized by hyperglycemia (high blood glucose thighs (a gynecoid pattern). The mechanism behind this breakdown in his ability to maintain normal lev- overweight male tends to have more of an els of blood glucose is, at least in part, a resistance by his triacylglycerol-rich adi- apple shape than the typical overweight female, who is more pear-shaped. Applebod has a hyperlipidemia (high blood cardiovascular disease, hyperinsulinemia, lipid level—elevated cholesterol and triacylglycerols), another risk factor for car- diabetes mellitus, gallbladder disease, diovascular disease. Applebod’s disorder is inferred from a stroke, and cancer of the breast and positive family history of hypercholesterolemia and premature coronary artery dis- endometrium. It also carries a greater risk of ease in a brother. Because more men than At this point, the first therapeutic steps should be nonpharmacologic. Apple- women have the android distribution, they bod’s obesity should be treated with caloric restriction and a carefully monitored are more at risk for most of these conditions. A reduction of dietary fat and sodium would be advised in an But women who deposit their excess fat in a effort to correct his hyperlipidemia and his hypertension, respectively. Upper body fat deposition tends to occur BIOCHEMICAL COMMENTS more by hypertrophy of the existing cells, whereas lower body fat deposition is by dif- Anthropometric Measurements. Anthropometry uses measure- ferentiation of new fat cells (hyperplasia). In adults, the measurements most commonly used are: height, weight, ing weight. In infants and young children, length and head circumference are also measured. Weight should be measured by using a calibrated beam or lever balance-type scale, and the patient should be in a gown or in underwear. Height for adults should be measured while the patient stands against a straight surface, without shoes, with the heels together, and with the To obtain reliable measures of head erect and level. The weight and height are used in calculation of the body mass skinfold thickness, procedures are index (BMI). For example, in the triceps measurement, a fold of skin in the Skinfold thickness. Over half of the fat in the body is deposited in posterior aspect of the nondominant arm subcutaneous tissue under the skin, and the percentage increases with midway between shoulder and elbow is grasped gently and pulled away from the increasing weight.