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By: Bertram G. Katzung MD, PhD

  • Professor Emeritus, Department of Cellular & Molecular Pharmacology, University of California, San Francisco


The protein that is produced as the results of this exon skipping is sufficient to purchase 25 mg microzide with amex function and to best microzide 25 mg reduce the severity of the disease order microzide 25 mg on line. Exon skipping does not seem to microzide 25 mg be a successful way to treat genetic diseases caused by a mutation in an enzyme. Many enzymes (including muscle glycogen phosphorylase) must form specific shapes to be active. Mutations at almost any place in the amino acid chain of muscle glycogen phosphorylase prevent correct formation or functioning of the muscle glycogen phosphorylase enzyme. It therefore seems that exon skipping would not be a suitable therapy for McArdle’s. However, no muscle glycogen phosphorylase activity was detected in this McArdle person. This natural experiment suggests that exon skipping wouldn’t work for McArdle people. Within mature skeletal muscle cells, the expression of many genes, including foetal genes, is prevented. In adult human skeletal muscle, foetal/brain glycogen phosphorylase is not produced. This protein could then replace muscle glycogen phosphorylase in the muscles of McArdle people. Valproate is commonly used as an anti-epilepsy drug which stabilises electrical activity in the brain, and is already approved for use in humans. Nine days after the injection there were 2861 muscle fibres which were expressing phosphorylase in the muscle which had been injected with valproate. There were 283 muscle fibres expressing phosphorylase in the muscle injected with saline. Since this could have been due to physical injury from the needle, an oral trial was carried out. McArdle’s lambs were given a drink of valproate 147 similar to the way in which humans take valproate. Preliminary results indicated that phosphorylase was present in some of the fibres (Howell, 2008). This treatment has a lot of promise as a therapy for McArdle’s, but further experiments will be needed to determine whether valproate also activates other proteins, which could have a negative effect. Notexin, a toxin from the tiger snake, damages muscle fibres, leading to regeneration. Regenerating fibres express the foetal/brain isoform of glycogen phosphorylase, but once they are mature, they stop expression of the foetal isoform, and switch to expression of the muscle isoform. Brain and liver isoforms of glycogen phosphorylase were expressed (McC Howell, 2008) due to damage from either the notexin or physical damage from the injection. The expression of the brain and liver isoforms of glycogen phosphorylase improved the strength and fatigueability of the muscle fibres in the treated McArdle sheep, although not totally. This is not a very practical form of treatment for McArdle people, as it would involve the use of a toxin which damages muscles and would involve frequent injections throughout skeletal muscles. One method is to put the gene for that enzyme into special cells in a laboratory which then use the gene to produce lots of enzyme. The enzyme is taken around the body in the bloodstream, and then taken into muscle cells. When muscle cells take up proteins from the bloodstream, they usually put them into the lysosome. Diseases caused by the lack of an enzyme in the lysosome can be treated because the cells take up the enzyme from the bloodstream and transport it into the lysosome. This therapy has aided cardiac muscle and extended the life of infant patients, but has been less effective in skeletal muscle than hoped. It was successful in decreasing the amount of glycogen stored in the skeletal muscle (Schoser et al. Gaucher disease is an autosomal recessive lysosomal storage disease caused by a deficiency in -glucocerebrosidase enzyme. Recombinant human replacement enzyme Cerezyme (made by Genzyme) is given intravenously and reduces the symptoms (Weinreb, 2008). Negative reactions such as anaphylactic shock, tachycardia, hypertension, chest and throat tightness, nausea, vomiting, rashes and headaches can occur during intravenous administration, which is initially conducted in a medical setting. There is no published data of any enzyme therapy being tried in people with McArdle’s or non-lysosomal defects (apart from oral treatment). Muscle glycogen phosphorylase is needed in the sarcoplasm/cytoplasm of the muscle cells, which is the wrong location. Anything which the cells take up is usually put into the lysosome, where they are broken down into smaller parts for reuse. This would not work for McArdle disease as the enzyme is needed in a different place; the cytoplasm/sarcoplasm. Some chemicals (called “pharmacological chaperones” or “active site inhibitors”) may be able to bind to muscle glycogen phosphorylase which contains a mutation. It may prevent the quality control system of the cell from recognising or destroying the protein. I have included therapies which at present are only theoretical, and have not yet been tested as potential treatments for McArdle’s. Some of these therapies have only been tested for a few different diseases at present, and are relatively new. Ten years is a relatively short period of time for a therapy to be explored by scientists and to become a treatment used for patients.

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I understand that it is not practical like read ing a “how-to” article or something like that order microzide 25 mg free shipping. I think ction helps you be a better person because it helps you under stand people order microzide 25mg mastercard. For example buy 25 mg microzide overnight delivery, in the Bluest Eye generic microzide 25 mg, at the end of the story we understand why the people do the things that they do. We judge the characters right away but then we learn about them and maybe change our judgment. Fiction can also help us have a good imagination, and this is important in helping us be creative. It may not be practical, like reading the newspaper, however it is a lot more fun and helps me be a better person. Like you and me, wondering, is fun things a waste of time too, or only do the practi cal what you should Some people think that school cafeterias should be required to provide low-fat and/or vegetarian lunch options to accom modate the eating habits of all students. Sample 6 Score It’s a fact: There are students across the United States who are vegetar ian and/or health conscious, and school cafeterias should be required to provide low-fat and/or vegetarian lunch options for them. Even more importantly, many teenagers’ dietary decisions are not only based on health concerns but also religious and/or moral issues. Just by reading headlines in any of the major news magazines, it becomes clear that the United States is a nation that needs to slim down. In every town and city, there are an abundance of fast food restaurants that lure teenage customers with fast, inexpensive, and tasty food, but these foods are typically unhealthy. Unfortunately, school cafeterias, in an effort to provide food that is appetizing to young people, mimic fast food menus, often serv ing items such as burgers and fries, pizza, hot dogs, and fried chicken. While these foods do provide some nutritional value, they are relatively high in fat, and many of them, namely burgers, hot dogs, and fried chicken, are clearly not designed for vegetarians. Many of the lunch selections currently offered by most school cafeterias could be made vegetarian and/or more healthy with a few simple and inex pensive substitutions. Veggie burgers, for example, offered alongside beef burgers, would give both vegetarians and the health conscious more options. A salad bar woud also serve the dual purpose of providing both veg etarians and low-fat food eaters the opportunity for a satisfying meal. This is not to say that accommodating every desire or food preference is plausi ble, but students should have the right to be served foods that coincide with their life choices. In addi tion, there are people who choose to eat low-fat foods, either to lose weight or to stay healthy. Many of these people are students who eat lunch at their 39 501 Writing Prompts school cafeterias on a daily basis. Surprisingly though, school cafeterias are not required to provide low-fat nor vegetarian options for students. Unfortunately, vegetarian options may be limited to the french fries (served with burgers) or pizza. While these are vegetarian (non-meat) options, they do not necesarily serve as low-fat foods. I think schools should have a wider variety of low-fat and/or vegetarian options such as a salad bar, or perhaps even something with tofu. The food at schools are bad enouf and then why should they hafe to have stuff that those people like. Many people feel that the use of surveillance cameras in public places such as parking lots is a good idea that can help ensure our safety. Sample 6 Score Not long ago, the nation was gripped by the horrifying news that a baby had been stolen from a car in a parking lot while her mother, who was return ing a shopping cart, was just a few feet away. Thanks to the description of the kidnapper captured by surveillance cameras in the parking lot and broadcast over radios, television, and highway overpass signs, the kidnap per was quickly caught and the baby returned, unharmed, to her mother. Had it not been for those surveillance cameras, that mother would proba bly never have seen her baby girl again. I can’t think of a much better argument for the use of surveillance cam eras in public places. Many people worry about the use of surveillance cameras in public places such as parking lots, stores, parks, and roadways. They worry that the information captured on 40 501 Writing Prompts the surveillance tapes can somehow be used against them. It seems to me that the only reason we should worry about being caught on surveillance cameras is if we are doing something wrong. If we are behav ing lawfully in a public place, then why worry if it is captured on lm One, they can help us nd those who commit crimes, including thieves, kid nappers, vandalizers, and even murderers. A thief who plans to steal a car may think twice if he knows he will be caught on video. A woman who hopes to kidnap a child may abandon her plans if she knows she will be captured on lm. Surveillance cameras can also help us in less critical but nonetheless prac tical ways. In some towns in England, for example, radio deejays use infor mation from surveillance cameras to announce the availability of parking spaces in crowded public parking lots. Problems of all shapes and sizes can also be noted and addressed through video surveillance. Reviewing the lms, ofcials might realize that people who meet in the square move quickly into the shade of the one tree in the center of the square. This could move ofcials to plant more trees or provide tables with umbrellas so that people could meet and relax in the shade.

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Femoral neck fractures may occur occa fractures may be worthwhile if the tumour occu sionally in young patients through normal bone cheap 25 mg microzide visa, pies more than 50% of the diameter of the bone discount microzide 25 mg overnight delivery. The incidence of septic arthritis of ing that the femoral neck breaks without a fall the hip in intravenous drug abusers appears to buy microzide 25 mg visa be at all! Surgical drainage is usually the time of injury is all important in determining necessary order 25mg microzide. Ultrasound scanning may be required to the ultimate outcome of all femoral neck fractures. The Intracapsular fracture joint surfaces are destroyed, and the capsule this type of fracture occurs through the femoral becomes distended with pus. A history of through to the surface of the skin, forming a sinus, a fall is common, and the patient will be unable to which may become secondarily infected. Early mobilization is essential Painful soft-tissue conditions around to avoid the complications of long periods con the hip ned to bed. Two methods of surgical treatment Trochanteric bursitis is a self-limiting inamma are available: tion of the bursa between the greater trochanter 1 Reduction of the fracture and internal xation. The condition is characterized the fracture is reduced on the operating table by pain over the tip of the greater trochanter, under X-ray control, and two to three screws are rather than pain in the groin, and usually settles passed across the fracture to stabilize it (Fig. In dis placed fractures it is preferable to remove the ball of the femur, and replace it with a prosthesis. An allows controlled collapse of the fracture when the Austin Moore or Thompson’s implant is often patient is weight-bearing to encourage union of used, to allow early weight-bearing (Fig. As the fracture heals, some shortening Total hip replacement may be preferable in may occur. Fractures of the femoral shaft Intertrochanteric fractures these fractures are ‘extracapsular’ and occur in the these fractures are seen in all age groups. The frac wide metaphyseal region between the two tro ture may occur at various levels in the shaft of the chanters in the femur. Because the blood supply to femur, and is frequently an open injury and associ the fracture is adequate, such fractures tend to ated with other injuries. Patients present in a fracture can often be signicant, and blood replace similar way to those with subcapital fractures, ment may be necessary. Injuries to the femoral and and X-ray diagnosis is usually straightforward sciatic nerve occasionally occur. The immediate treatment of a femoral shaft frac Internal xation of intertrochanteric fractures ture is the application of a Thomas splint (see Fig. Such a device and the resulting stability aids in reducing blood 185 Chapter 21 the hip and thigh Figure 21. Modern intramedullary nails are often made of titanium, and allow immediate mobiliza tion. Full weight-bearing is usually possible from 34 weeks after intramedullary nailing. Anterior cruciate ligament rupture is commonly associated with fractures of the femoral shaft. Fractures of the distal femoral shaft and loss from the fracture, and in providing comfort for supracondylar fractures the patient. Gallows traction is a simple method of applying traction in a child aged up to 2 years (see these fractures are often displaced by the action of Fig. The treat the preferred treatment of femoral shaft frac ment of such fractures is commonly surgical, and a tures is xation with an intramedullary nail. Intra intramedullary nail is inserted under X-ray control medullary nail xation is possible, the nail being from the greater trochanter, passed down across passed through the knee, across the fracture, and 186 the hip and thigh Chapter 21 Figure 21. The acetabular fracture may lary nail xation is good provided bone quality is be through the back, the oor or, less commonly, adequate. The patient presents with fragments are held together with screws connected the leg exed, adducted and shortened, and the to a plate applied to the side of the femur. The plates may be inserted through relatively small sciatic nerve, particularly the lateral popliteal divi incisions and serve to ‘bridge’ the fracture site. It is carried out under the hip joint is anatomically strong, but disloca general anaesthesia with the patient lying supine, tion can occur, usually as a result of considerable preferably on the oor or a low couch, and by violence. These injuries are often caused by car exing the hip and simply lifting the head of the accidents in which a front seat traveller is involved femur into the joint. Once reduced, it is usually in a head-on collision and strikes his/her knee stable and the leg is then held on longitudinal skin under the dashboard. Depending on the degree of traction for 3 weeks to allow the capsule to heal, exion of the hip, a simple dislocation may occur followed by a further 3 weeks of protected weight or there may be a fracture dislocation involving the bearing. The patient with a painful knee usually Applied anatomy walks with the knee held stify and quickens the the knee is not a simple hinge joint. The femoral step on the affected side, a so-called antalgic condyles are of different lengths and exion occurs gait. A patient with a fused knee has difculty by a mixture of gliding and rolling of the condyles swinging the leg through and will circumduct on the tibia. Rotation of the tibia is important at (swing the leg out) or ‘vault’ (rise up on the the end of extension as the femur is screwed into standing leg) to stop the foot hitting the ground. A ‘locked’ knee is one which will not extend the menisci are the ‘shock absorbers’ of the knee fully. Abduction and adduction deformities are and share the load transmitted across the joint. If these deformities are long healing only occurs if the meniscus is detached standing they predispose to arthritis.

Explain to microzide 25 mg without prescription the patient that there are possible late complications of blood transfusions and that they should notify medical personnel immediately if the develop signs or symptoms of late complications buy microzide 25 mg otc. Signs are fever proven 25mg microzide, mild jaundice purchase 25 mg microzide fast delivery, gradual fall in hemoglobin level, positive Coombs’ test. Bacterial infection: A few contaminating bacteria, particularly gram-negative, can grow in refrigerated blood and may cause severe reactions and sepsis if transfused. Procedures that allow blood to reach room temperature (prolonged transfusions or warming blood) may accelerate bacterial growth and are potentially hazardous. What Not To Do: Do not continue a transfusion when a patient complains of difficulty breathing and feeling bad during a transfusion. Stop the transfusion, continue normal saline, and evaluate for possible transfusion reaction. Do not reassure a patient that all transfusions are completely safe and without risk. Transfusion is preferred when the benefit of the transfusion, out weighs the risk of the complications. Infusion of fluids, blood or medications into the tibia of a child or the sternum of an adult is the only route available (rare in adults since, central venous access is usually possible). The single recommended site of insertion for adults is the manubrium (top 1/3 of the sternum), or on the midline and 1. Use a boring or screwing motion to advance the needle distally (away from the epiphysial plate) at a 45° angle until it penetrates into the marrow. To check your needle placement, aspirate bone marrow into 10 cc syringe filled halfway with sterile saline. Cannot aspirate: Apply just enough pressure to plunger to clear needle tip of possible clot/bone particle, then aspirate again. Swelling around injection site: indicates penetration of bone has not occurred and saline is being injected into fleshy tissue; reassess and try again. What You Need: A large Kelly clamp, a needle holder, tissue forceps, a mosquito clamp, appropriate sutures and needles or pre-package suture/needle combinations (preferred), four towel clamps, sterile gloves, several 4x8 inch gauze pads, four hand towels, shaving razor, antiseptic solution and sponges, irrigation syringe (may use attached catheter for increased pressure), sterile saline for irrigation and suture wash, surgical bowl(s), a 22-23 gauge needle with 5-10 cc syringe, and lidocaine anesthesia (with or without epinephrine as appropriate). They are easier to handle and tie than plain suture, have higher tensile strength, and cause less tissue reaction. Good tensile strength, minimal tissue reaction (5) Polyester or Polypropylene: Not absorbable. Stainless steel is the strongest suture material, with the most secure knots, and is well tolerance by tissue unless corroded. Suture, especially braided suture, can provide a wick through the skin allowing pathogens access to a wound. Thread needles with desired suture if not using pre-packaged needle/suture combinations. Insert the point of the needle perpendicular to the skin and then follow the curve of the needle through when piercing tissue. Go deeper rather than wider with the stitches if need to achieve greater wound closure. Keep stitches uniform approximately 5-10mm apart and 5-10mm from the wound edge, with knots away from the wound edge. Simple interrupted suture: Puncture the skin with the needle and exit into the wound, traversing the skin only. Pull the needle out through the wound, and enter the opposite side of the wound at the same depth. Advantages: strength; successive sutures can be placed following the path of the laceration; distance, depth and tissue eversion can vary from stitch to stitch (see Figure 8-1). Vertical mattress suture: Puncture the skin with the needle at least 1 cm from the edge of the wound, and exit into the wound, traversing the skin and subcutaneous tissue (at least 1 cm deep). Pull the needle out through the wound, and enter the opposite side of the wound at the same depth (subcutaneous tissue). Curve the needle up through the skin at least 1 cm from the edge of the wound, positioning it as on the other side. Point the sharp tip away from yourself and insert the needle approximately 5mm from the wound. Disadvantage: constricts blood supply at wound edges, possibly causing necrosis and dehiscence. Suture continuously the entire length of the wound without tying any additional knots until the end. This method can be modified to ‘lock’ each stitch by bringing the suture back across the wound after the stitch and passing it under the piece of suture coming from the previous stitch. Advantages: aligns perpendicular to the wound, distributing tension evenly; allows watertight, rapid closure; locking feature prevents continuous tightening of the stitches as suturing progresses. Disadvantages: not able to adjust to tension from edema; should not be used on areas of existing tension (see Figure 8-1). Eliminate the dead space by rolling the wound proximally to distally with a rolled gauze pad. Apply bacitracin or other topical antibiotic as appropriate and then bandage the wound. Tell the patient when to return to have the sutures removed or to return earlier if the wound shows signs of infection (red, hot, swollen, wound draining pus; fever; red streaks from wound). Remove stitches from eyelid in 3 days; cheek in 3-5 days; nose, forehead and scalp in 5-7 days; arm, leg, hand, foot in 7-10+ days; and chest, back, and abdomen in 7-10+ days. What Not To Do: Do not suture opposite sides of the wound at different depths or distances from the wound edge. This will create uneven skin alignment, overriding edges and poor or delayed healing, as well as a poor cosmetic result. Do not tie sutures too tight, so as to compromise blood flow to the wound edges, which need it most.

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