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As the knowledge of epigenetic mechanisms in human diseases expands order vytorin 30mg online, it is expected that approaches to disease prevention and therapy using epigenetic interventions will also continue to develop and may eventually become mainstays in disease management buy 30 mg vytorin with visa. Recent advances in epigenetic-based methods have served as major driving forces in the fascinating and ever-expanding epigenetic phenomena that have been revealed especially over the past decade order vytorin 30mg free shipping. Combinations of epigenetic technologies are also emerging that show promise in leading to new advances in understanding the epigenetics of disease. Epigenome refer- ence maps will likely have an impact on our understanding of many different diseases and may lead the way to breakthroughs in the diagnosis, prevention and therapy of human cancers. Epigenetic therapy for cancer is perhaps one of the most exciting and rapidly developing areas of epigenetics. The development of drug-based inhibitors of these epigenetic-modifying enzymes could be further improved through drug combinations or even natural plant-based products, many of which have been found to harbor properties that can mimic the often more toxic and perhaps less bioavailable epigenetic drugs that are currently in use. At this point, however, the number of neurodevelopmental disorders that have been associated with epigenetic aberrations is not very extensive. In fact, many neurodevelopmental disorders are due to partial loss-of-function mutations or are X-chromosomal mosaics with recessive X-linked mutations. Neurodegenerative diseases such as Alzheimers disease have been increasingly associated with alternations in epigenetic processes. These factors may begin early in life and manifest as late-onset forms of Alzheimers disease. Epigenetic processes are central to aging and are also an important mediator between the environment and disease and it is thought that these factors may be important in the development and progression of numerous autoimmune diseases. However, both epigenetic and genetic factors are often important in human imprinting disorders and the development of epigenetic therapy approaches in this particular area represents a considerable challenge. Advances are being made in understanding the epigenetic basis of human imprinting disorders which may provide breakthroughs in treating these tragic diseases. It is likely that increased identication of obesity biomarkers and their associated epigenetic factors may lead to new advances in controlling the extant epidemic in childhood obesity in many developed countries. However, multisystem studies are currently needed to further substantiate this concept and additional studies on the prediction and prevention of type 2 diabetes are sorely needed. Additionally, this transgenerational component may allow for the transmittance of epigenetic changes to future generations beyond the offspring leading to allergic disorders. Novel early interventions into epigenetic-modifying factors such as maternal diet may contribute to an eventual decline in allergy-based disorders. Future efforts are now being directed toward modiers of other epigenetic processes in allergic disorders such as histone phosphorylation and ubiquitination. The consequences of these epigenome-modifying infections are not limited to neoplasia. There are, in fact, many other diseases that have an epigenetic basis induced by infectious agents such as diseases of the oral cavity. Knowledge accumulated regarding epigenetic invaders of the genome and their pathological consequences will undoubtedly lead to the development of more sophis- ticated and novel approaches to controlling and treating epigenetic-based infectious diseases. These ndings may have important epigenetic therapeutic implications for endometrial cancer and could also have potential for the prevention, diagnosis and risk assessment of endometrial cancer. Chromatin modications and dynamics appear to have an important role in conservation of pluripotency and the differentiation of embryonic stem cells which are central factors in stem cell-based therapeutics. Understanding the basic epigenetic changes central to these processes may have considerable potential in the treatment of human epigenetic diseases. Although aging is not considered a disease in and of itself, it is perhaps the most frequent contributor to human disease. Therefore, delaying the epigenetic aberrations associated with aging through epigenetic intervention and treating epigenetic-based age-associated diseases could have a tremendous impact on the role of epigenetics in human disease. The role of nutrition, hormones and metabolic environment early in life can have effects throughout life, inuence epigenetic pathways and markers and manifest in the form of aging and age-related diseases. Consid- erable interest is now focused on the impact of early life epigenetic impacts and the outcome of these effects on the myriad of age-associated diseases which comprise much of the pathology that forms the basis of human disease. These diseases, that can be loosely grouped under the heading of epigenetic diseases, are vast and the list of diseases that t into this description is rapidly growing. A common theme of many epigenetic-based human diseases is the role of the environment. Exciting advances are rapidly developing that are contributing signicantly toward the management of human diseases through epigenetic intervention. It is anticipated that epigenetic-based preventive and therapeutic strategies will continue to develop at a rapid pace and may assume a role at the forefront of medicine in the not too distant future. The Drosophila Fab-7 chromosomal element conveys epigenetic inheritance during mitosis and meiosis. Much of our increased understanding is the result of technological breakthroughs that have made it feasible to undertake large-scale epigenomic studies. In turn, we have a growing understanding of the consequences of aberrant patterns of epigenetic marks and of mutations in the epigenetic machinery in the etiology of disease. However, there are several aspects of the methods used to analyze epigenetic variation associ- ated with disease that present potential problems. This depends to some extent on the nature of the disease, and can inuence the analytical methods that are employed. Second, different diseases may require analysis of either regional or genome-wide epigenetic variation, with the choice depending on the predicted variation in the specic disease. The continuing increase in the number of epigenetic diseases means that the list of methods that are practical for the different diseases is also increasing. Therefore, use of strategies that can differentiate the role, or otherwise, of 8 epigenetic variation in the causality of a disease is fundamental. Although the new technologies have provided considerable insights into epigenetic aspects of disease, there is still considerably more work that needs to be carried out. The availability of detailed epigenetic maps will be of enormous value to basic and applied research and will enable pharmacological research to focus on the most promising epigenetic targets. This chapter summarizes some of the contemporary methods used to study epigenetics and highlights new methods and strategies that have considerable potential for future epigenetic and epigenomic studies. The use of restriction enzymes that are sensitive to CpG methylation within their cleavage recognition sites [6] is a relatively low-resolution method, but it can be useful when combined with genomic microarrays [7,8]. This approach is therefore generally regarded as the gold-standard technology for detection of 5-methyl cytosine as it enables mapping of methylated sites at single-base-pair resolution [9]. However, the modied nucleoside 5-methyl cytosine is immune to transformation and, therefore, any cytosines that remain following bisulte treatment must have been methylated. This method is currently one of the most popular approaches to methylation analysis and yields reliable, high-quality data [9,10]. The drawback to the method is that it is labor-intensive and is not suitable for screening large numbers of samples. The various advantages and disadvantages of this approach have been reviewed previously [11e13]. Recent high-throughput studies have used protein afnity to enrich for methylated sequences and then exploited these sequences as probes in genomic microarrays. This protocol can be carried using multiplex reactions, thus enabling the simultaneous quantication of multiple CpG sites in each assay. Thus, while very sensitive, this assay may be more suited to laboratory diagnosis.

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Myoblast is a term designating a myogenic cell that is fully 31 determined with respect to its myogenic phenotype order vytorin 20mg overnight delivery. Early during development purchase 30 mg vytorin free shipping, 32 multinucleated myotubes are formed by proliferating myoblasts buy discount vytorin 20 mg on-line, which withdraw 33 from the cell cycle and fuse with one another. Myoblasts continue to be added to 34 these myotubes allowing them to expand in both length and girth to become mature 35 muscle fibres (Edom et al. Thus during development and postnatal growth, 36 nuclei are added to the muscle fibres by the fusion of myoblasts to the parent fibre. If 39 the quiescent state of satellite cells were a delicate equilibrium between electrical 40 activity, growth factors and extra-cellular matrix composition, disequilibrium of the 41 environment would trigger activation and proliferation of satellite cells. Following 42 a muscle trauma, the satellite cells proliferate and either form new muscle fibres or 43 repair damaged fibres via a process equivalent to muscle histogenesis (Bischoff and 44 Heintz, 1994). A number of factors are 03 involved in this regulation of satellite cell activation (Hawke and Garry, 2001). Maximum 08 force, which increases up to the age of thirty, then decreases by an average 15% per 09 decade as of the age of fifty and by an average 30% after the age of seventy. This 10 decrease in force appears to be greater in the leg muscles than in the arm muscles. On the other hand, a decrease of 1% 12 per year is observed in the maximum level of oxygen uptake (V02max) as of the 13 age of thirty (Le Page et al. Muscle mass decrease by between 35 and 40% between the ages 16 of twenty and eighty, representing 1. Moreover, this age-related loss of muscle mass appears preferentially to 18 affect the lower part of the body. This muscular atrophy results from both a loss of 19 individual muscle fibres as well as from a decrease in fibre diameter estimated at 20 1. Muscle atrophy is accompanied by an increase in the amount of non-contractile tissue: intramuscular 22 fat and conjunctive tissue (Lexell et al. Communication between the muscle 23 fibres and the blood vessels is less efficient: there are fewer blood capillaries in 24 the muscle and this leads to reduced oxygen uptake, which partially explains the 25 decrease in V02max (Hepple et al. A decrease in muscle oxidative capacity is also observed, 27 and this contributes to the decreased V02max and increased fatigability (Degens, 28 1998). Increased fibrosis not 29 only hinders communication between the muscle fibres and the blood vessels, but 30 also causes stiffening of the muscle, thereby contributing to alterations in muscle 31 function (Gosselin et al. Moreover, the regenerative capacity of muscle 32 tissue also appears to alter with age (Vignaud et al. The neurotransmitter then binds to its receptor 02 located on the muscle cell membrane and induces the formation of an electric current 03 across the membrane. Excitation-contraction coupling is defined as the biological 04 phenomenon that transforms an order arriving in the form of an electrical signal 05 into a mechanical event: contraction of the muscle cell. These two binding molecules constitute channels 11 through which the calcium passes and whose opening is controlled by the electric 12 current. In effect, it has been 17 shown that the number of calcium channels diminishes with age (Delbono, 2003). However, experiments carried out on isolated human muscle cells 21 moderate this theory. The experimental results obtained in vitro on muscle fibres 22 from different subjects in which the reservoirs had been rendered inactive show a 23 drop in developed force in the fibres of elderly subjects compared to that of young 24 subjects (Frontera et al. This 26 would indicate that excitalion-contraction decoupling is not the limiting factor in 27 the loss of developed force with age. The number and the force of the actin-myosin 28 crossbridges appear to be the preponderant factors. Nevertheless, it 35 cannot be excluded that this reduction may modify the expression of the genes 36 encoding myosin, for example, which would lead to a modification in the actin- 37 myosin cross-bridges. The cause-and- effect relationship should be explored in 38 more detail in the forth coming years. It has however been shown that the 39 myosin molecule is susceptible to post-translational modification such as glycation. It could therefore be imagined that physical activity can 42 maintain the number of functional receptors and thus maintain sufficient expression 43 of the muscle genes, thereby making it possible to maintain a high level of force 44 production. Type I fibres have the 05 greatest number, followed by Type lla, and finally Type llx fibres. In addition to 06 this heterogeneous number of mitochondria in muscle cells, it is interesting to note 07 that regular physical activity increases the number of mitochondria in the cells. As 08 previously discussed, the main effects of age on skeletal muscle are sarcopenia and 09 cell death. Free radicals cause severe damage if 13 they are not promptly eliminated by the action of anti-oxidant agents. It is undeniable that cells accumulate mutations 23 with age, but not all these mutations induce modifications in mitochondrial activity. We can add 25 to this argument by saying that the mutations that trigger cell death disappear and 26 that the muscle cells reformed by satellite cells no longer present these mutations. The first experiments 29 carried out on patients suffering from mitochondrial myopathies type pathologies 30 are encouraging (Chabi et al. It is already well know that physical activity 31 improves endurance capacities in healthy subjects, but the same also appears to 32 be true for myopathic patients. One part of the activated satellite cells does 43 not differentiate and renews the stock of quiescent satellite cells. The satellite cells 44 are involved in maintaining the fibre size/muscle nuclei ratio. Modification, with age, in the capacity of satellite cells 04 to proliferate or fuse could be another factor limiting the action of repairing these 05 cells and of maintaining muscle mass during the aging process. The proportion of satellite cells we found in corresponding 15 muscles in aged persons (mean age: 74 4 25 years) were relatively low; 1. We have 17 also examined in the same way the number of satellite cells in the vastus lateralis 18 of four subjects with a mean age of 88 years. This suggests 20 that there is a significant decrease in the satellite cell number between young and 21 old adults for three different muscles. Further analysis is needed to find out if there 22 is a progressive decrease in satellite cells number during adulthood or whether at 23 some critical time there is a sudden decrease due to altered trophic enviroment 24 in the aged muscle. To obtain this knowledge it will be necessary to carry out a 25 transversal analysis. This 33 suggests that human satellite cells are not lineage restricted, and that the regulation 34 of the program they can express is open and will depend on external factors such 35 as innervation (Edom et al. One should keep in mind that although human 36 muscle contains in general mixed fibres, the ratio of which is specific for each 37 muscle, there are no specific fast and slow satellite cell lineages in human skeletal 38 muscle. Since human satellite cells upon differentiation are not oriented towards a 39 precise fibre type programme this will allow them to participate in the growth and 40 repair of any fibre in their vicinity regardless of its programme of differentiation 41 (Mouly et al. During their life span human cells will gradually replicate more slowly 03 until they reach a non replicative state called replicative senescence. We have 04 studied the number of divisions that human satellite cells can make when they are 05 isolated from donors of different ages.

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The several weeks safe 20mg vytorin, weakness develops cheap vytorin 20 mg otc, in the limb and the distribution varies depending on what of the first or second rib may be the cause of a lower gene defect localizes to chromosome 17 30 mg vytorin overnight delivery. Involvement of the lower trunk causes weakness in muscles innervated by C8 and T1 roots. Weakness is present in both median nerve and ulnar nerve innervated intrinsic hand muscles and medial wrist flexors. Contraindications Neuralgic amyotrophy Corticosteroids do not alter the course of the Known hypersensitivity to narcotic drugs. Upper brachial plexus Immune rachial plexus neuropathy: lesions recover more quickly. Weakness in the suggestive evidence for inflammatory-immune diaphragm and serratusanter ior are associated pathogenesis. To based on clinical, radiographic, and pain, and later with progressive weakness and distinguish from plexopathy it is important to look electrodiagnostic differences. Preferential Age vessel injury with subsequent lumbosacral plexus involvement of the sacral plexus results in more infarction. There may also be a direct toxic effect prominent weakness below the knee, and Many etiologies for lumbosacral plexopathy involvement of the gluteus medius and of the cisplatin on the plexus. Sex Preferential involvement of the lumbar plexus chemotherapeutic agents has also been reported to result in a lumbosacral plexopathy. Radiation-induced lumbosacral plexopathy lumbosacral plexopathies and are often Patients with cancer infiltration present with back and occurs in women, but is also seen in young men after associated with a pelvic fracture. Radiation cancers) or from distant sites (breast and thyroid a greater degree in retroperitoneal plexopathies become more likely with a higher total carcinoma, sarcoma, and lymphoma), and diabetes hemorrhage. Some patients heparin therapy, and roughly 50/0of patients on have a significant degree of weight loss. Late irradiation-induced suspected of having a retroperitoneal hemorrhage lesions of the lumbosacral plexus. Lumbar plexus neuropathy sacrum, and lumbosacral vertebrae in cases of resulting from retroperitoneal hemorrhage. Diabet ic lumbosacral plexopathy and to distinguish Precautions proximal neuropathy: clinical and between neoplastic and radiation etiologies. Patients with retroperitoneal hemorrhage, diabetic amyotrophy, neuralgic amyotrophy of the lumbosacral plexus, and postobstetrical plexopathy tend to improve over time. While patients with diabetic amyotrophy + Management have a good recovery, only 40% make a full functional recovery. Neoplastic infiltration is If a tumor is identified, radiation treatment may be typically associated with a poor prognosis, indicated depending on the tumor type. If the although early treatment results in a better patient is on heparin, this should be discontinued outcome. Surgical evacuation for retroperitoneal hemorrhage is controversial and most patients are treated conservatively. Cell count does not can involve the anterior horn cells of spinal cord usually exceed 500 cells/mm3, initially and motor nuclei of cranial nerves Acute causes of peripheral neuropathy polymorphonuclear leukocytes shifting to Guillain-Barr syndrome with resultant paralysis. Symptoms resolve completely in Nerve conduction velocities are usually normal; most patients. Paralysis of voluntary motor unit potentials; and fibrillation belonging to the Picornaviridae family. It has three develops 2 to 5 days after abortive polio when potentials appear at about 3 weeks. Symptoms start with fever, headache, and muscle As improvement occurs, giant motor units spreads through food or drink contaminated by pain. When forced vital capacity decreases below Exercise instability, bladder and bowel dysfunction) can be 12 mL/kg (less than 1 to 15 L for adults) or significant Adult age (>18 years) seen. Symptoms include dysphagia, Bulbar functions should be followed and aspirations paralytic disease. Long- Vaccine-associated paralytic polio There are no surgical procedures for the acute term sequelae include weakness, atrophy of limb; Postpolio syndrome and growth failure especially in young children. For chronic phase correction of scoliosis; tendon lengthening and transfers are examples of rehabilitative surgeries. As improvement may continue up to 2 years, surgical procedures should be postponed until this time. Committee on Infectious Diseases of the eradicated from a large part of the world. An hygiene and sanitation, and immunization are In the acute phase, respiratory exercises, hot additional dose can be administered at 6 months important to prevent and eradicate polio infections. Immunization programs should be continued until prevent contractures should be performed. Active Immunization programs in countries where polio has the disease is eradicated all over the world even in exercises and occupational therapy can be started been eradicated may employ combined areas free of polio, at the subacute phase. Post-polio syndrome: concepts Patients in the convalescent phase of system and shedding in stool in clinical diagnosis, patho genesis and etiology. Ten percent of paralytic cases die due to respiratory and bulbar Update on adult immunization. In bulbar poliomyelitis cases Recommendations of the Immunization - I n addition to serum humoral immunity, mortality goes up to 60%. This condition is called " malignancy, and lowered resistance due to postpolio syndrome. The syndrome is characterized by systemic lupus erythematosus, rheumatoid Antibodiespatterns of antibody production primary inflammation of skeletal muscle with arthritis, antisynthetase syndrome, and mixed may provide additional support for clinical myofiber necrosis; other organs may be connective tissue disease. A viral etiology has myopathies D-penicillamine been speculated but not demonstrated. Perinatal Muscle pain/tenderness may occur Inflammation is perivascular, perimysial, and mortality approaches 60% in the few cases Dysphagia endomysial. Such potential complications considered for dysphagia refractory to p (within 12 months) been on glucocorticoids. Myositis Association of Physical therapy and occupational therapy response to the drugs), hypertension, should be considered to preserve range of America, Inc. If azathioprine is iheffective, consider methotrexate 15 to 25 N/A mg/week orally. American Hospital Recommendations about following creatine weeks, followed by a slow taper over 10 weeks to 1 Formulary Service. In severe cases, Society of Health-System Pharmacists, 1995:2094- examination is the best measure of progress 2102. J Med 1991;325: pressure, serum glucose, and potassium, and eyes reduced by 5 or 10 mg every 3 to 4 weeks until the 1487-1498. A new approach to the Corticosteroids are contraindicated in patients dihydrofolatereductase) with folk acid 5 mg classification of idiopathic inflammatory myopathy: with a known hypersensitivity to any of the once weekly after the methotrexate dose. Obstet Gynecol Sury 1998;44: Precautions bodies, and a delay in, or inadequate, treatment. Both agents inhibit the heme biosynthetic Inddence Attacks of acute intermittent porphyria pathway. Glucose is given in doses of 300 g per day manifest themselves as acute attacks of abdominal pain, and heme in the form of hematin hme albumin, or Porphyria has an incidence of approximately 1 in 50, which is poorly localized and may be associated with heme arginate at doses of 3 to 4 mg per day for 4 000.

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If there is a good Divide between the 4th & 5th segments of the sacrum cheap 20 mg vytorin overnight delivery, chance of improving function order vytorin cheap online, and at the same time removing tumour with the coccyx and 5th sacral segment buy generic vytorin. Good clearance is necessary, do not be tempted to remove extra digits until a child is and this is difficult when the tumour is wrapped closely older (32. Mobilize the tumour completely, and then incise the skin at its lower border with another Chevron, some distance above the anus, and so remove the teratoma. Repair the levator ani (26-1) behind the rectum and hitch it up to the presacral fascia. Close the skin in an inverted Y shape with 4/0 nylon, with a suction drain in situ, and it leave it usually in place for 48hrs. A surgical scar, especially if it is on the face, should be nearly invisible if made along Langers lines (34. Suggesting a keloid (34-1D): onset delayed for Sometimes a scar becomes very visible indeed as the result months/yrs, invasion of the surrounding skin, growth stops of hypertrophy and keloid formation. If diagnosis is difficult, remember that a keloid becomes Both a hypertrophic and a keloid response are more likely increasingly raised, and extends beyond the confines of the if a wound is infected, contaminated by foreign material original scar. Midline sternal & abdominal scars and longitudinal incisions in the arm are particularly likely to develop keloids: they cross skin creases. Maintain careful asepsis, minimize trauma when you operate, and control bleeding carefully at the end of the operation. If a patient is particularly likely to develop a hypertrophic scar or a keloid, as shown by his previous history, apply pressure to the scar for 9-12months after an operation. This may not be practical, but you may be able to cut a piece of foam rubber to fit a Fig. Both patients had laparotomies smaller scar, and hold it in place with an elastic bandage. After Bowesman C, Surgery and Clinical Pathology in the Tropics, Livingstone, 1960 with kind permission. Within 1-2months of the injury: the approach to their treatment depends on whether it is (1) Apply pressure. The worse the keloid, the main problem is in the skin or the muscle & joint the more likely it is to recur if you excise it. Avoid sutures: infections and arthritis of all kinds will lead to muscle and use steristrips. All this is difficult, as is closing the wound Such may require repeated complex interventions which tidily. Postoperatively administer contractures by using a distracting external fixator at a rate 4 more steroid or triamcinolone injections at 3wkly of 2mm/day (32. Apply a pressure bandage or an elastic garment releasing a skin contracture, but may well avoid complex for 9 months: this is essential! If you are persistent and careful, you will not find them as difficult to treat in a district hospital as you might expect. You have skin loss to cope with, so they are more difficult than polio contractures (32. Insist on taking graft dressings off yourself: do this gently, with much soaks of water! Contractures of the larger joints are not too difficult, but those of the hand are tasks for an expert; yet you may have to try. C, the plane through which than those on the back of the hand, where the mcp joints to remove it. Surgery and Clinical Pathology in the Tropics, readily become hyper-extended, as part of a claw hand. It is wise not to try to excise contractures widely without excising them, then graft the the scar initially, either in the main part of the contracture, bare area with a medium or thick split skin graft. Make children your first priority: you will be much less (3),Contractures will take more extensive incisions to successful with adults. Do not try to relieve burns contractures by using serial (4) Beware of congested veins, especially in the axilla and casts (32. Carry the incision beyond the limits of the scar tissue, and beyond the axes of the joint on each side. Or, make a double-Y (34-5D); this will reduce the length of the incision you need to make. When the contracture is straightened out, you will need more skin than you expect. Cover the bare area with a sheet split skin graft, and suture it in place preferably with a tie-over dressing. Immobilize the area carefully, with splints or plaster of Paris in the position of full release of the contracture. This will reduce the risk of the contracture recurring, and the risk of infection reaching the joint. Maintain a regular review; you may need to make serial releases with several operations. D, a broad If the chin is contracted down on the sternum (34-3), contracture which needs excision and skin grafting. To prevent recurrence, keep the (1) demonstrate the tissue planes more clearly, neck in extension. Apply a soft collar as soon as the skin is (2) allow you to separate the scar more easily, soundly healed, and leave it there for at least 6months. Try to restore full abduction and elevation in a single If there are flexion contractures of the fingers, incise operation. If there is a broad contracture, incise the scar as them transversely maximally taking care not to damage above, and abduct the arm. Apply a large medium the digital nerves & arteries, and fill the gap with a full thickness split-skin graft to the bare areas, and secure it thickness, or a thick split-skin graft sutured into place. Cover this with plenty of dry For a child, splint the fingers in extension for 3months, wool, and bandage this (preferably with crepe bandages) or the contracture will recur. To help the cast stay in place, to include the whole arm as well as the axilla and chest. Examine the cast daily at first, and later weekly, to make sure it has not slipped. In a small child, a large ball of cotton wool bandaged into For an adult, do not immobilize the extended fingers for the axilla may hold the arm in the right position. Follow the general method, as described above, taking (1) Do not injure the axillary vessels or nerves. If there is an ulcer within a scar, think of squamous If you have found the right fatty plane, this should free up carcinoma: excise it with adequate margins and send it for the scar tissue. You are operating A Z-plasty is a useful way of releasing a contracture, for a flexion contracture so lack of flexion will not be a if it is narrow enough. If the contracture is mild, a dynamic splint may cure it, Make a Z-plasty by excising the scar and then cutting or at least partially correct the deformity, so that operation 2 flaps in the form of isosceles triangles which share one will be easier.