David Robertson MD

• Elton Yates Professor of Medicine, Pharmacology and Neurology
• Vanderbilt University
• Director, Clinical & Translational Research Center, vanderbilt institute for Clinical and Translational Research, Nashville

https://ww2.mc.vanderbilt.edu/neurology/26258

Molecular pathways: current role and future directions of the retinoic acid pathway in cancer prevention and treatment menstrual cup reviews provera 5 mg online. Role of bexarotene in the treatment of cutaneous T-cell lymphoma: the clinical and immunological sides women's health clinic barrie discount 5mg provera otc. Using multiple targeted therapies in oncology: considerations for use women's health clinic north adelaide buy provera with a mastercard, and progress to date in breast cancer womens health 8 veggie burgers purchase provera 5 mg online. Efficacy of intensitymodulated radiotherapy combined with chemotherapy or surgery in locally advanced squamous cell carcinoma of the head-and-neck menstrual distress questionnaire buy provera us. Systematic chemotherapy for inoperable womens health robinwood hagerstown md buy provera 5mg fast delivery, locally advanced, recurrent, or metastatic uterine leiomyosarcoma: a systematic review. Timing of adjuvant systemic therapy and radiotherapy after breastconserving surgery and mastectomy. Comparative clinical benefits of systemic adjuvant therapy for paradigm solid tumors. Neoadjuvant chemotherapy and targeted therapy in breast cancer: past, present, and future. Neoadjuvant therapy for localized prostate cancer: examining mechanism of action and efficacy within the tumor. Nanotechnology approaches for personalized treatment of multidrug resistant cancers. Enhancing immunotherapy using chemotherapy and radiation to modify the tumor microenvironment. Ingestion of selenium and other antioxidants during prostate cancer radiotherapy: a good thing Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy The impact of personalized medicine on survival: comparisons of results in metastatic breast, colorectal and non-small-cell lung cancers. The emergence of drug transportermediated multidrug resistance to cancer chemotherapy. Mechanisms of drug resistance in cancer chemotherapy: coordinated role and regulation of efflux transporters and metabolizing enzymes. Synergism from sequenced combinations of curcumin and epigallocatechin-3-gallate with cisplatin in the killing of human ovarian cancer cells. Development of therapeutic combinations targeting major cancer signaling pathways. The use of drugs to modify immune responses, or immunomodulating agents, is therefore an important area of pharmacology. By contrast, it is sometimes necessary to suppress immune function pharmacologically to prevent immune-mediated injury to certain tissues or organs. Immunosuppressive drugs, or immunosuppressants, can prevent the rejection of transplants or treat specific diseases caused by an autoimmune response. Nonetheless, immunosuppressive agents are often lifesaving because of their ability to prevent and treat organ rejection and to decrease immune-mediated tissue damage in other diseases. The group of drugs that increase immune function, or immunostimulants, is rather small and the clinical use of immunostimulants is limited when compared with the indications for immunosuppressive drugs. However, the development and use of immunostimulants is an exciting area of pharmacology, and some insight into the therapeutic use of these drugs is provided. Physical therapists and occupational therapists may be involved in the rehabilitation of patients who have received organ transplants, skin grafts, or similar procedures that necessitate the use of immunosuppressant drugs. Rehabilitation specialists also treat patients with autoimmune disorders or immunodeficiency syndromes that affect the musculoskeletal system; these patients are also likely to be taking immunomodulating drugs. Hence, this chapter will provide therapists with knowledge about the pharmacology of these drugs and how their effects and side effects can affect physical rehabilitation. The immune response consists of two primary components: innate and adaptive (acquired) immunity. Macrophages engulf and process antigens and present these antigens to T lymphocytes (T cells). These mediators activate other lymphocytes (B cells) and cause these cells to differentiate into plasma cells, which produce various antibodies. T cells continue to replicate and proliferate, thus producing more lymphokines, which further amplifies the T-cell effects. These lymphokines also recruit lymphocytes derived from bone marrow-that is, B cells. Plasma cells ultimately release specific antibodies known as immunoglobulins (IgG, IgA, IgM, etc. Clearly, the immune response is an intricate sequence of events that involves a complex interaction between a number of cellular and humoral components. The overview provided here is just a brief summary of how some of the primary components participate in mediating acquired immunity. The references at the end of this chapter provide sources for more information on this topic. First, the immune response is often attenuated pharmacologically following the transplantation of organs or tissues to prevent the rejection of these tissues. Often, several different types of immunosuppressants are used together in fairly high doses to prevent or treat transplant rejection. Of course, giving several powerful drugs at high doses often causes unpleasant or even toxic side effects. These effects must often be tolerated, however, considering the limited number of organs available for transplantation and the need to ensure the survival of the transplant as much as possible. Nonetheless, drugs that suppress the immune system can limit damage to various other tissues, and these drugs may produce dramatic improvements in patients with diseases that are caused by an autoimmune response. Azathioprine (Imuran) is a cytotoxic agent that is structurally and functionally similar to certain anticancer drugs, such as mercaptopurine. Azathioprine appears to act like the antimetabolite drugs used in cancer chemotherapy (see Chapter 36). Impaired nucleic acid synthesis slows down the replication of lymphocytes and other key cellular components that direct the immune response. The primary side effects of azathioprine are related to suppression of bone marrow function, including leukopenia, megaloblastic anemia, and similar blood dyscrasias. Cyclophosphamide (Cytoxan, Neosar) is an anticancer alkylating agent that is commonly used in a variety of neoplastic disorders (see Chapter 36). Cyclophosphamide is used very cautiously as an immunosuppressant because of the possibility of severe side effects, including carcinogenic effects during long-term use. Cyclosporine (Neoral, Sandimmune) is one of the primary medications used to suppress immune function following organ transplantation. Cyclosporine is used to a somewhat lesser extent in treating autoimmune diseases, but it may be helpful in conditions such as psoriasis, rheumatoid arthritis, inflammatory bowel disease, autoimmune hepatitis, and glomerulonephritis. Cyclosporine and tacrolimus (see below) are known as calcineurin inhibitors because they inhibit a specific protein (calcineurin) in lymphoid tissues. By inhibiting calcineurin, cyclosporine ultimately suppresses T-cell activation, thus limiting the ability of T cells to produce other chemical mediators that promote immune cell activity. The primary problem associated with cyclosporine is nephrotoxicity, which can range from mild, asymptomatic cases to severe kidney dysfunction, which requires discontinuation of the drug. These problems, however, tend to be less severe with cyclosporine than with other less-selective immunosuppressants. As described in Chapter 29, glucocorticoids are powerful anti-inflammatory and immunosuppressive drugs. Glucocorticoids exert a rather nonspecific inhibition of virtually all aspects of celland chemical-mediated immunity, thus enabling these drugs to be used in a variety of situations when it is necessary to suppress immune function. In some cases, the glucocorticoid may even be withdrawn during maintenance immunosuppressive therapy, and nonsteroidal drugs (cyclosporine, tacrolimus, mycophenolate mofetil) are used to provide long-term immunosuppression following organ transplantation. Methotrexate (Folex, Rheumatrex) was originally developed as an anticancer agent (see Chapter 36), but this drug is also used in certain noncancerous conditions that have an autoimmune component. This agent has only mild immunosuppressive effects, however, and is not typically used to treat organ transplants or other conditions that require more extensive immunosuppression. This interference produces a general inhibition of the replication of lymphocytes inherent in the immune response. The major problems associated with methotrexate include hepatic and pulmonary toxicity. These problems are dose-related, however, and serious adverse effects tend to occur less frequently at doses used for immunosuppression than at those used for anticancer treatment. Although their exact mechanism of immunosuppression is unclear, glucocorticoids probably interrupt the immune response by a complex effect at the genomic level of various immune cells. Hence, these drugs disrupt the production of chemical signals that activate and control various immune system cellular components. For more details about how glucocorticoids exert their effects on various cells and tissues, see Chapter 29. The immunosuppressive effects of glucocorticoids are balanced by several side effects. As described in Chapter 29, glucocorticoids typically produce a catabolic effect on collagenous tissues, and the breakdown of muscle, bone, skin, and various other tissues is a common adverse effect. Glucocorticoids also produce other side effects, including hypertension, adrenocortical suppression, growth retardation in children, an increased chance of infection, glaucoma, decreased glucose tolerance, and gastric ulcer. These side effects can be especially problematic when glucocorticoids are used to prevent transplant rejection because these drugs are often given in high dosages for extended periods. To lessen the side effects, glucocorticoids are typically combined with other nonsteroidal immunosuppressants, such as cyclosporine, azathioprine, or immunosuppressive antibodies, so that synergistic effects can be obtained and immunosuppression can be achieved with relatively low doses of each drug. Mycophenolate mofetil (CellCept) is primarily used to prevent or treat organ rejection following cardiac and renal transplantation. This drug is typically combined with other immunosuppressants (cyclosporine, glucocorticoids) to provide optimal immunosuppression in patients receiving these transplant types. The primary adverse effects associated with mycophenolate mofetil are blood disorders. Sulfasalazine (Azulfidine, others) has unique properties, with some antibacterial characteristics similar to sulfonamide drugs (see Chapter 33) and some anti-inflammatory characteristics similar to the salicylates (see Chapter 15). This drug is primarily used to suppress the immune response associated with rheumatoid arthritis and inflammatory bowel disease. The exact mechanism of this drug in immune-related disorders is not fully understood. These drugs were approved originally to treat renal cell cancer but may also be successful in suppressing immune responses. Sirolimus and its analogs are used primarily to prevent organ rejection in people with solid organ transplants (kidney, heart, etc. These drugs also exert several other beneficial effects, including the ability to inhibit smooth muscle proliferation in blood vessel walls. For this reason, sirolimus and everolimus are sometimes incorporated into drug-eluting stents-a supportive tubular structure (stent) is placed in the lumen of a partially occluded artery, and the drug is released slowly from the stent to help reduce vessel occlusion. Sirolimus and its analogs may cause blood lipid disorders, including hypercholesterolemia and hypertriglyceridemia, and may also impair wound healing. Tacrolimus is used primarily to prevent rejection of kidney and liver transplants. This binding provides a somewhat more selective inhibition of immune function than other drugs that exert a general or nonselective inhibition of the immune response. Researchers have also developed antibodies that are very selective for antigens located on the surface of specific T cells and other lymphocytes; these antibodies inhibit cell function or cause destruction of the cell. For example, agents have been developed that block the interleukin-2 receptor, thus preventing interleukin-2 from activating T lymphocytes. Finally, the use of fusion proteins is another strategy for affecting specific immune functions. Antibodies used in rheumatoid arthritis are addressed in more detail in Chapter 16. Fusion proteins basically block the receptor on the T cell that receives the second (co-stimulatory) signal, hence suppressing T-cell activation. Other fusion proteins are in development, and these drugs may provide an effective strategy for modifying immune responses in specific diseases. In summary, immunosuppressant antibodies and fusion proteins continue to gain acceptance as a method for preventing rejection of transplanted tissues and for treating various autoimmune diseases. The pharmacology of these drugs, which are used primarily as anticancer agents, is described in more detail in Chapter 36. Their use as immunosuppressants has generally declined in favor of drugs that have a more selective and strategic effect on immune function. Nonetheless, these drugs may be helpful in certain autoimmune disorders or in preventing the rejection of tissue and organ transplants in specific situations. Nonetheless, thalidomide may help blunt immunological responses by regulating the genes that express tumor necrosis factor-alpha. Likewise, it may be difficult to selectively stimulate certain aspects of the immune system to treat a specific problem without also causing a more widespread and systemic immunologic response. Nonetheless, a few strategies are currently available to modify or stimulate immune function in a limited number of situations. This drug, however, may not be effective in the most common strains of mycobacterium that cause tuberculosis, and its use as a vaccine may also be limited by other side effects. Some evidence suggests that it may activate macrophages locally at the site of the cancer and that these macrophages engulf and destroy tumor cells. When administered directly into the bladder, common side effects include bladder irritation and infection. However, there has been considerable interest in developing pharmacological methods to modify or even stimulate immune function in specific situations. Immune globulin (Gamimune, Gammagard, others) is prepared by extracting immunoglobulins from donated human blood. Immune globulin is administered intravenously to boost immune function in several conditions, including primary immunodeficiency syndromes. Commercial preparations of immune globulin mimic the normal role of endogenous immunoglobulins.

Sclerotherapy under ultrasound or x-ray guidance is useful for macrocystic lesions or macrocystic portions of the tumor but is generally unsuitable for microcystic tumors pregnancy 16 weeks order genuine provera on-line. If the ultrasound suggests abnormal thyroid anatomy breast cancer hereditary order provera with a visa, thyroid scintigraphy may be performed womens health yuma az order genuine provera. Excision of the cyst alone has been found to lead to unacceptably high rates of recurrence women's health center greensboro nc cheap provera 10mg with amex, ranging from 38% to 70% pregnancy 0-8 weeks purchase provera in india. Surgical excision via a Sistrunk procedure is the recommended procedure women's health center saskatoon buy provera 10 mg cheap, to minimize the chance of recurrence. In this procedure, the cyst is removed along with the central portion of the hyoid bone and the entire thyroglossal duct, which tracks from the pyramidal lobe of the thyroid gland to the foramen cecum at the base of the tongue. Recurrence using this technique in the literature ranges from the thyroid, from the foramen cecum at the base of the tongue to its distal position at the pyramidal lobe of the thyroid gland. Presentation typically involves progressive lateral neck swelling, with varying degrees of erythema. Because the implicated pathogen in most acute cases is Staphylococcus aureus or Streptococcus pyogenes and the increasing incidence of methicillin-resistant and clindamycin-resistant S. When culture results are not available, local antibiograms may be useful in determining antibiotic susceptibility. Plain films may demonstrate radiopaque stones, although this cannot be ruled out with a negative study. Sialography is a simple technique and may be considered to evaluate the ductal system in recurrent cases, although this may be poorly tolerated in young children. Recurrent sialadenitis may indicate obstruction of the salivary duct by stones, strictures, or scar tissue. Small stones near the duct orifice may be removed in the office in compliant patients via incision of the duct to the location of the stone. In proximal obstruction, ductal dilation with or without sialoendoscopy may be performed. Stones and mucous plugs may be removed Bacterial sialadenitis is an infection of the salivary glands, most commonly seen in the submandibular and parotid glands. Patients typically report several days of progressive unilateral pain and swelling of the affected gland, which worsens with eating and chewing. There may be a prior history of intermittent swelling of the gland, which raises suspicion for salivary duct stones or strictures. The increasing prevalence of clindamycin resistance in Staphylococcus aureus isolates in children with head and neck abscesses. Increased isolation of methicillinresistant Staphylococcus aureus in pediatric head and neck abscesses. To drain or not to drain- Management of pediatric deep neck abscesses: A case-control study. The incidence of this condition is 1/700 live births making it the most common birth condition in the United States. In fact, some studies show that an increasing prevalence may be occurring in this country, especially in women over the age of 35. The tongue is not as large as it appears but is located in the small oropharynx and oral cavity, giving the appearance of macroglossia. Several features, including the presence of epicanthal folds, a relatively large tongue, and single palmar creases, suggest the diagnosis. Conductive hearing loss can also be an issue relating to Eustachian tube dysfunction or to ossicular abnormalities. Monitoring of growth and development should be done on separate growth charts existing for children with trisomy 21, as height and weight expectations are different. Otolaryngologic care includes determination of hearing and addressing breathing issues. Otologic care includes optimization of hearing, as conductive hearing loss can be corrected with tubes, when appropriate, hearing amplification, or surgery. The relative macroglossia and small oropharynx predispose to a higher incidence of obstructive sleep apnea. Pierre Robin, a French stomatologist, was not the first to describe this association, since St. Hilaire reported a case over 100 years prior, but he is credited for bringing the condition to prominence and demonstrating the significant negative impact of its features. The sequence is felt to originate with mandibular hypoplasia, which then leads to glossoptosis causing airway obstruction and cleft palate. Mandibular hypoplasia may result from external deformational causes or intrinsic malformation. Unfortunately, there is no set definition for what constitutes pathologic mandibular hypoplasia in the infant, and some degree of relative mandibular hypoplasia is considered normal. Despite this, it is generally felt to be one of the more common birth anomalies occurring between 1/3,000 and 1/14,000. The condition must be differentiated from other craniofacial syndromes with known micrognathia. Bedside clinical airway evaluation with or without laryngoscopy by the neonatologist and pediatric otolaryngologist may be sufficient for the mild to moderately affected cases early on. More severely affected cases or those with complicated courses may require intubation accompanied by direct laryngoscopy and bronchoscopy to direct therapy. Assessment and cooperation with a speech therapist specializing in infant feeding are beneficial. Airway stabilization interventions are not primarily aimed at improving feeding, and some successfully treated for airway compromise will still need gavage support. Fortunately, the need for gastric tube nutrition rarely continues after the first year of life. Nonsurgical airway management is successful in the great majority of cases, perhaps as many as 70%. Prone or lateral positioning with airway monitoring may be sufficient without additional measures in half of affected children. Discontinuation of therapy is considered once the pediatric otolaryngologist determines the airway is sufficiently improved. Prior to surgical therapy, direct laryngoscopy and bronchoscopy are required to evaluate for degrees of tongue base obstruction, laryngomalacia, tracheomalacia, or bronchial stenosis. Mandibular distraction osteogenesis is a surgical means of increasing posterior airway space by elongating the mandible and thereby advancing the tongue. Over the course of one to three weeks, the mandible can be incrementally elongated with internal or external devices. Depending on the technique, distraction procedures may place at risk developing tooth buds, the trigeminal nerve sensory innervation of the lower lip and chin, and the marginal mandibular motor innervation to the lower lip. Tracheostomy remains the gold standard for complete relief of airway obstruction, but morbidity and mortality remain real concerns. The incidence of a cleft of the lip with or without palate varies considerably based on geography and racial variability. The defect occurs as a result of a failure of the median nasal process to fuse with the maxillary process during the sixth week of development. The subsequent structural abnormalities have implications for both form and function that may negatively affect deglutition, respiration, speech, hearing, occlusion, facial appearance, and psychosocial development. Since surgical interventions may have negative effects on growth, a staged surgical approach throughout childhood is required triggered by specific developmental goals. The affected facial structures in the nasolabial cleft are displaced and variably hypoplastic, but largely present. Disruption of the nasolabial musculature is marked by abnormal orientation and insertion of the cleft side transverse muscles of the nose, levator muscles of the upper lip, and orbicularis oris muscle complex. Splaying of the alar base, inferior displacement of the alar rim, deviation of the nasal tip, and irregularity of the caudal nasal septum characterize the typical resulting nasal deformity. Abnormal fibrous insertions exist between the lateral crus of the lower lateral cartilage and the lateral piriform rim on the cleft side. In the Craniofacial Disorders 441 bilateral cleft lip, the nasal tip is depressed, and the premaxillary segment can be variably displaced. The upper jaw is deformed by the osseous discontinuity at the nasal base and dental alveolus, and dental anomalies are common. A missing lateral incisor is the most common finding occurring about 50% of the time, and missing second premolar teeth on the side of the cleft are increased in incidence as well. The etiology of most isolated clefts of the lip is thought to be heterogeneous and multifactorial including genetic factors and environmental. Any associated anomalies or positive history should trigger the involvement of a pediatric geneticist for more comprehensive assessment. The full weight of evaluating the cleft patient is distributed throughout childhood and into adolescence with interdisciplinary contributions that are simultaneously applied, but variably emphasized. Early in childhood, hearing, speech development, and dental health assessments predominate. The child with a cleft of the lip will require surgery to reorient and reconstruct the cutaneous structures of the upper lip and oral mucosa, the musculature of the oral sphincter and nasal base, and the nasal cartilaginous framework. The rotation advancement technique popularized by Millard remains the most common approach to primary surgical intervention for the unilateral cleft. In this approach, the medial cleft margin is rotated down and the repair incision inferiorly matched to the expected position of the philtral column. The lateral cleft lip is advanced to meet the medial lip and to fill any deficiency of tissue high in the philtrum below the columella. A preserved C-flap can be used to minimize the need for this advancement below the columella or to augment the nasal floor reconstruction. When a palatal cleft is present, treatment proceeds as noted in the "Cleft Palate" section. Since the development of the upper jaw is embryologically related to the upper lip, it is expected that bone graft construction of the cleft maxilla and palate will be beneficial in almost all patients with a cleft lip. In any case where there is insufficient bone to support erupting teeth, bone grafting is required. The primary objectives of bone grafting are to unify the maxilla, close any oronasal fistula, provide adequate bone to support eruption and orthodontic treatment of adult teeth, and provide appropriate nasal base support and symmetry. The ideal time for treatment is when the developing adult tooth adjacent to the cleft has a root that is half to two-thirds formed. In addition to these primary reconstructions, some children will benefit from secondary interventions. Normalization of lip and nasal form may require a soft tissue revision of lip scars and proportions later in childhood. The incidence of a cleft palate alone is closer to 1 in 2000, and interestingly, the occurrence is homogenous across racial populations. The defect occurs as a result of a failure of the palatal shelves to fuse or maintain fusion in the midline of the maxilla. The subsequent structural abnormalities have implications that may negatively affect deglutition, respiration, speech, hearing, occlusion, facial appearance, and psychosocial development. To optimally address the complexity of effects, a multidisciplinary approach blending therapy and surgery is required. The affected oral structures in the palatal cleft are displaced and variably hypoplastic, but largely present. Disruption of the palatal musculature is dominated by abnormal orientation and insertion of the levator veli palatini, tensor veli palatini, and palatopharyngeus and palatoglossus muscles. Veau first recognized this in his cadaver studies where he described the "cleft muscle" and the understanding greatly enhanced in clinical practice by Kriens description of intravelar veloplasty. The primary palate constitutes the maxilla and dental structures anterior to the incisive foramen and is formed by the same facial processes that form the lip and nose. The secondary palate includes the hard and soft palate tissues posterior to the incisive foramen and is distinct from the primary palate. An isolated cleft palate is complete if it extends into the hard palate approximating the incisive foramen; otherwise, it is considered incomplete. A submucous cleft palate exists when the triad of bifid uvula, hard palate notching, and midline zona pellucida is present without an overt palatal cleft. Stickler syndrome is notable for ocular findings, hearing loss, midface deficiency, and arthritis. Cleft palate alone is notable for having a much greater association with syndromes, sequences, or additional malformations, occurring in approximately Initial evaluation for the child born with a cleft of the palate should include a thorough family history and clinical exam. Any associated anomalies or positive history should trigger the involvement of a pediatric geneticist for more comprehensive assessment and possible genetic testing. Early in childhood, hearing, speech development, and dental health assessments are most critical. Middle childhood often represents a transition to maxillofacial and orthodontic management. The two most common techniques for closure of the palate with muscular reconstruction are the straightline closure with intravelar veloplasty and the double-opposing Z-plasty technique of Furlow. In the straight-line closure, the hard palate may be closed with an early vomerine flap as advocated by Sommerlad, by lateral releasing incision in the style of von Langenbeck, or by two complete flaps pedicled off the descending palatine vessels as described by Bardach. The soft palate is closed in three layers with oral and nasal mucosa lining, a retrodisplaced levator veli palatini, and palatopharyngeus muscle sling. It is critical to separate this muscle unit from the posterior hard palate, from soft tissue attachment to the tensor aponeurosis, and from abnormal mucosal attachment to allow adequate reconstruction of the velopharyngeal muscle sling. Another means of accomplishing the same end is with doubleopposing Z-plasty flaps. Myringotomy with placement of tubes is effective for treating Eustachian tube dysfunction, when present, and regular hearing checks, otoscopic exam, and tympanograms are necessary for longitudinal monitoring. In addition to the primary reconstruction, all children benefit from regular developmental assessment by speech and language pathologists.

Generic provera 10mg visa. Download Magazine for FREE (MagazinesDownload org).

In addition to its normal role in controlling fluid and electrolyte balance women's health clinic taos nm buy 10mg provera with visa, abnormal aldosterone production can have detrimental effects on the cardiovascular system womens health haverhill discount provera uk. It has long been understood that increased aldosterone production can promote renal sodium and water retention menopause no period purchase provera paypal, thus leading to hypertension and heart failure pregnancy jobs cheap 10mg provera with visa. For example women's health & family services cheap provera 5 mg on line, mineralocorticoid receptors exist in the brain womens health 15 minute workout order provera with paypal, and these receptors are normally involved in the central control of salt and water balance. Abnormal activation of these receptors may lead to systemic changes associated with hypertension. Furthermore, there is considerable evidence that excess aldosterone production is associated with metabolic syndrome, a condition characterized by increased hypertension, insulin resistance, hyperlipidemia, and increased abdominal fat storage (see Chapter 21). On a cellular level, excess or prolonged aldosterone production can cause inflammation, hypertrophy, and fibrosis of cardiac, vascular, and other tissues, thus leading to detrimental changes in these tissues that can lead to cardiovascular problems and perhaps other diseases. Mineralocorticoid and glucocorticoid replacement is usually required in patients with chronic adrenocortical insufficiency (Addison disease), following adrenalectomy, and in other forms of adrenal cortex hypofunction. Fludrocortisone (Florinef) is the primary aldosteronelike agent for replacement therapy. This compound is chemically classified as a glucocorticoid, but it has high levels of mineralocorticoid activity and is used exclusively as a mineralocorticoid. Adverse Effects of Mineralocorticoid Agonists the primary problem associated with mineralocorticoid agonists is hypertension. Because these drugs increase sodium and water retention, blood pressure may increase if the dosage is too high. These problems are also caused by the effects of these drugs on electrolyte and fluid balance and are usually resolved by adjusting the dosage. These drugs are competitive antagonists of the aldosterone receptor-that is, they bind to the receptor but do not activate it. When bound to the receptor, these drugs block the effects of endogenous mineralocorticoids (aldosterone) by preventing the aldosterone from binding to renal cells and other tissues. Consequently, spironolactone and eplerenone antagonize the normal physiological effects of aldosterone, resulting in increased sodium and water excretion and decreased potassium excretion. Physicians administer spironolactone and eplerenone primarily as diuretics when treating hypertension and heart failure. These drugs are classified as potassium-sparing diuretics because they help increase sodium and water excretion without increasing the excretion of potassium (see Chapter 21). The patients take the drug for several days to antagonize the effects of excessive aldosterone production. When the drug is discontinued, serum potassium levels will decrease sharply if hyperaldosteronism is present-that is, plasma potassium levels will fall when aldosterone is again permitted to increase potassium excretion. As indicated above, mineralocorticoid antagonists, such as spironolactone and eplerenone, can help decrease the detrimental effects of aldosterone on the kidneys, heart, vasculature, and other tissues. However, it appears that eplerenone has a lower incidence of these sexual side effects, and it may preferentially suppress mineralocorticoid function without also affecting the sex hormones. Special Concerns for Rehabilitation Patients Adrenal steroids play an important role in the pharmacological management of many patients seen in rehabilitation. Physicians often treat systemic conditions such as rheumatoid arthritis, ankylosing spondylitis, and lupus erythematosus with glucocorticoid drugs (see Table 29-2). More localized musculoskeletal conditions, such as acute bursitis and tenosynovitis, may also be treated for short periods with glucocorticoids. Because these conditions are often being treated simultaneously in a rehabilitation setting, therapists must be especially cognizant of the effects and implications of glucocorticoids. The primary aspect of glucocorticoid administration that concerns therapists is the catabolic effect of these hormones on supporting tissues. As discussed previously, glucocorticoids cause a general breakdown in muscle, bone, skin, and other collagenous structures. The glucocorticoid-induced catabolism of these tissues can be even greater than expected in the presence of other contributing factors such as inactivity, poor nutrition, and the effects of aging. For instance, a certain amount of osteoporosis would be expected in an elderly, sedentary woman with rheumatoid arthritis. Strengthening activities help maintain muscle mass and prevent severe wasting of the musculotendinous unit. In general, any activity that promotes mobility and ambulation will be beneficial during and after glucocorticoid therapy. Therapists must use caution, however, to avoid injuring structures that are weakened by glucocorticoid use. The load placed on the musculoskeletal system must be sufficient to evoke a therapeutic response but not so excessive that musculoskeletal structures are damaged. The difference between therapeutic stress and harmful stress may be rather small in some patients taking glucocorticoids; therapists must use sound clinical judgment when developing and implementing exercise routines for these patients. Because glucocorticoids also cause thinning and wasting of skin, therapists should make extra efforts to prevent skin breakdown in patients on prolonged glucocorticoid therapy. Other aspects of prolonged adrenocorticoid administration also concern physical therapists and occupational therapists. Therapists should be aware of the sodium- and water-retaining properties of both glucocorticoids and mineralocorticoids. When used in acute situations or in long-term replacement therapy, both groups of adrenal steroids may cause hypertension. Therapists should routinely monitor blood pressure in patients taking either type of agent. Therapists must be especially cautious about exposing these patients to any possible sources of infection. Finally, therapists should be alert for any other signs of toxicity to adrenal steroids, such as mood changes or psychoses. Therapists may recognize the early stages of such toxic reactions and prevent serious consequences by alerting medical staff. She has involvement of many joints in her body, but her knees are especially affected by this disease. During periods of exacerbation, she receives physical therapy as an outpatient at a private practice. The therapy typically consists of heat, ultrasound, range of motion, and strengthening activities to both knees. During a recent exacerbation, her symptoms were more severe than usual, and she began to develop flexion contractures in both knees. Upon noting the severe inflammation, the physician elected to inject both knees with a glucocorticoid agent. Methylprednisolone (Depo-Medrol) was injected into the knee joints, with each joint receiving 40 mg of the drug. Glucocorticoid administration produced a dramatic decrease in the swelling and inflammation in both knees. The therapist considered initiating aggressive stretching activities to resolve the knee flexion contractures and restore normal range of motion. How can the therapist increase joint movement without causing injury to the joint These hormones are synthesized from cholesterol within cells of the adrenal cortex. The primary glucocorticoid produced in humans is cortisol (hydrocortisone), and the primary mineralocorticoid is aldosterone. Glucocorticoids exert several effects, such as regulation of glucose metabolism, attenuation of the inflammatory response, and suppression of the immune system. Mineralocorticoids are involved primarily in the control of fluid and electrolyte balance. Pharmacologically, natural and synthetic adrenal steroids are often used as replacement therapy to resolve a deficiency in adrenal cortex function. Patients also take glucocorticoids primarily for their antiinflammatory and immunosuppressive effects on a diverse group of clinical problems. These agents can be extremely beneficial in controlling the symptoms of various rheumatic and allergic disorders. Prolonged glucocorticoid use, however, is limited by a number of serious effects, such as adrenocortical suppression and breakdown of muscle, bone, and other tissues. Physical therapists and occupational therapists should be especially aware of the potential side effects of glucocorticoids. The role of morning basal serum cortisol in assessment of hypothalamic pituitary-adrenal axis. Gene profiling reveals a role for stress hormones in the molecular and behavioral response to food restriction. Blunted serum and enhanced salivary free cortisol concentrations in the chronic phase after aneurysmal subarachnoid haemorrhage-is stress the culprit Separating transrepression and transactivation: a distressing divorce for the glucocorticoid receptor Mineralocorticoid and glucocorticoid receptors at the neuronal membrane, regulators of nongenomic corticosteroid signalling. Steroid treatment alters adhesion molecule and chemokine expression in experimental acute graft-vs. The regulation of leucocyte transendothelial migration by endothelial signalling events. Comparison of surgical decompression and local steroid injection in the treatment of carpal tunnel syndrome: 2-year clinical results from a randomized trial. Efficacy comparisons of the intraarticular steroidal agents in the patients with knee osteoarthritis. Multiple pulley rupture following corticosteroid injection for trigger digit: case report. The effects of dexamethasone on human patellar tendon stem cells: implications for dexamethasone treatment of tendon injury. Glucocorticoid-induced diabetes and adrenal suppression: how to detect and manage them. Duration of cortisol suppression following a single dose of dexamethasone in healthy volunteers: a randomised double-blind placebocontrolled trial. Glucocorticoid-induced osteoporosis: an update on current pharmacotherapy and future directions. Delineating the receptor mechanisms underlying the rapid vascular contractile effects of aldosterone and estradiol. Aldosterone, mineralocorticoid receptor and the metabolic syndrome: role of the mineralocorticoid receptor antagonists. Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension. Mineralocorticoid receptor antagonists: emerging roles in cardiovascular medicine. Management of hyperkalaemia consequent to mineralocorticoidreceptor antagonist therapy. Exercise training prevents hyperinsulinemia, muscular glycogen loss and muscle atrophy induced by dexamethasone treatment. Role of exercise therapy in prevention of decline in aging muscle function: glucocorticoid myopathy and unloading. The neuropsychiatric complications of glucocorticoid use: steroid psychosis revisited. Non-genomic actions of aldosterone: from receptors and signals to membrane targets. Male hormones, such as testosterone, are usually referred to collectively as androgens. Androgens, estrogens, and progestins are classified as steroid hormones; their chemical structure is similar to those of the other primary steroid groups, the glucocorticoids and mineralocorticoids (see Chapter 29). In the female, the ovaries are the main sites of estrogen and progestin production. As discussed in Chapter 29, small amounts of sex-related hormones are also produced in the adrenal cortex in both sexes, which accounts for the fact that low testosterone levels are seen in females, and males produce small quantities of estrogen. However, under normal conditions, the amounts of sex-related hormones produced by the adrenal cortex are usually too small to produce significant physiological effects. In this chapter, we first discuss the physiological role of the male hormones and the pharmacological use of natural and synthetic androgens. We then address the physiological and pharmacological characteristics of the female hormones. There are several aspects of male and female hormones that should concern you as a physical therapist or occupational therapist. Rehabilitation patients may use these agents for approved purposes, such as female hormones as contraceptives. These agents may also be used for illicit reasons, such as the use of male hormones to enhance athletic performance. Hence, you should be aware of the therapeutic and potential toxic effects of these drugs. The seminiferous tubules are the convoluted ducts within the testes in which sperm production (spermatogenesis) takes place. Testosterone produced by the Leydig cells exerts a direct effect on the seminiferous tubules, as well as systemic effects on other physiological systems (see "Physiological Effects of Androgens"). For instance, growth hormone, thyroid hormones, insulin-like growth factor 1, and prolactin may also affect the functions of Leydig and Sertoli cells, thereby influencing the production and effects of testosterone. Testosterone enters the tubules to directly stimulate the production of sperm through an effect on protein synthesis within the tubule cells. Androgens and their synthetic derivatives are approved for administration in several clinical situations, ranging from common replacement therapy to rare hereditary disorders. Development of Male Characteristics the influence of testosterone on sexual differentiation begins in utero. In the fetus, the testes produce small amounts of testosterone that affect the development of the male reproductive organs. At the onset of puberty, a complex series of hormonal events stimulates the testes to begin to synthesize significant amounts of testosterone. The production of testosterone brings about the development of most of the physical characteristics associated with men.

Two of these iodinated tyrosines are then combined to complete the thyroid hormone menstrual extraction discount 5mg provera overnight delivery. The combination of a monoiodotyrosine and a diiodotyrosine yields triiodothyronine breast cancer updates buy 10mg provera otc, and the combination of two diiodotyrosines yields thyroxine womens health elkins wv buy generic provera 5 mg line. There has been considerable discussion about which hormone exerts the primary physiological effects women's health clinic fillmore provera 10mg sale. Plasma levels of T4 are much higher than T3 levels breast cancer 00 blogspot buy 5 mg provera visa, but T3 may exert most of the physiological effects on various tissues menstrual migraine headaches provera 10 mg with amex, which suggests that T4 is a precursor to T3 and that the conversion of T4 to T3 occurs in peripheral tissues. Addition of one iodine atom (I) to tyrosine produces monoiodotyrosine; addition of a second iodine atom produces diiodotyrosine. Thyroid follicle cells take up and concentrate iodide from the bloodstream-this is significant because there must be a sufficient amount of iodine in the diet to provide what is needed for thyroid hormone production. The hormones are then secreted into the systemic circulation, where they can reach various target tissues. Regulation of Thyroid Hormone Release Thyroid hormone production is controlled by the hypothalamic-pituitary system (see Chapter 28). Thyroid hormone release is subject to the negative feedback strategy that is typical of endocrine systems controlled by the hypothalamic-pituitary axis. In other instances, thyroid hormones appear to play a permissive role in facilitating the function of other hormones. For instance, thyroid hormones must be present for growth hormone to function properly. T4 and T3 increase the basal metabolic rate and subsequent heat production from the body, which are important in maintaining adequate body temperature during exposure to cold environments. Increased thermogenesis is achieved by thyroid hormone stimulation of cellular metabolism in various tissues, such as skeletal muscle, cardiac muscle, and liver and kidney cells. Thyroid hormones facilitate normal growth and development by stimulating the release of growth hormone and by enhancing the effects of growth hormone on peripheral tissues. If thyroid hormones are not present, severe growth restriction and mental retardation (cretinism) ensue. Thyroid hormones appear to increase heart rate and myocardial contractility, thus leading to an increase in cardiac output. It is unclear, however, if this occurrence is a direct effect of these hormones or if the thyroid hormones increase myocardial sensitivity to other hormones (norepinephrine and epinephrine). For instance, these hormones increase intestinal glucose absorption and increase the activity of several enzymes involved in carbohydrate metabolism. Thyroid hormones enhance lipolysis by increasing the response of fat cells to other lipolytic hormones. In general, these and other metabolic effects help to increase the availability of glucose and lipids for increased cellular activity. Certain "nongenomic" effects, for example, could be mediated by an effect of thyroid hormones on non-nuclear receptors located on the cell surface, in the cytoplasm, or in the mitochondria. The clinical manifestations of hyperthyroidism and hypothyroidism are listed in Table 31-2. Although we cannot review the causes and effects of all the various forms of thyroid dysfunction at this time, this topic is dealt with elsewhere extensively. Hypothyroidism is usually treated by thyroid hormone administration (replacement therapy). This section discusses the general aspects and more common forms of hyperthyroidism and hypothyroidism, along with the drugs used to resolve these primary forms of thyroid dysfunction. Hyperthyroidism Hyperthyroidism (thyrotoxicosis) results in the increased secretion of thyroid hormones. One of the more common causes of hyperthyroidism is diffuse toxic goiter (Graves disease). Because of a genetic defect, antibodies are synthesized that directly stimulate the thyroid gland, resulting in exaggerated thyroid hormone production. Physicians may also administer various pharmacological agents to manage hyperthyroidism in various situations. Antithyroid Agents Antithyroid drugs, such as propylthiouracil (PropylThyracil) and methimazole (Tapazole), directly inhibit thyroid hormone synthesis. Antithyroid drugs work by inhibiting thyroid peroxidase (the enzyme that oxidizes iodide to enable it to bond to tyrosine residues) and by preventing the coupling of tyrosine residues within the thyroglobulin molecule. Although serious problems involving formed blood elements (agranulocytosis and aplastic anemia) may occur, the incidence of such problems is relatively small. Finally, excessive inhibition of thyroid hormone synthesis from drug overdose may cause symptoms resembling hypothyroidism, such as lethargy and feeling cold. In addition, iodide may cause a severe hypersensitive reaction in susceptible individuals. Therefore, other agents such as antithyroid drugs and beta blockers have somewhat replaced the use of iodide. High doses of iodide, however, may be useful in limited situations to temporarily control symptoms of hyperthyroidism a week or so before the surgical removal of the thyroid. In addition to treating hyperthyroidism, high doses of iodine can decrease the risk of thyroid cancer after exposure to radioactive fallout from nuclear disasters. Basically, high levels of stable (nonradioactive) iodide in the bloodstream will reduce the need for the thyroid gland to absorb additional (radioactive) iodide. The isotope then begins to emit beta radiation, which selectively destroys the thyroid follicle cells. Essentially no damage occurs to surrounding tissues because the radioactivity is contained within the thyroid gland. Thus, administration of radioactive iodine is a simple, relatively safe method of permanently ablating the thyroid gland and reducing excess thyroid hormone function. For instance, high iodide levels limit the uptake of iodide into thyroid follicle cells, inhibit the formation of T4 and T3, and decrease the secretion of the completed hormones from the thyroid cell. Although iodide is effective in treating hyperthyroidism for short periods, the effects of this drug begin to diminish after about 2 weeks of administration. Beta blockers may also be helpful as adjuncts to other medications such as antithyroid drugs. Beta blockers may be especially helpful in severe, acute exacerbations of thyrotoxicosis (thyroid storm). Hypothyroidism There are many forms of hypothyroidism, differing in their cause and age of onset (see Table 31-1). Severe adult hypothyroidism (myxedema) may occur idiopathically or may be caused by specific factors such as autoimmune lymphocytic destruction (Hashimoto disease). In the child, thyroid function may be congenitally impaired, and cretinism will result if this condition is untreated. Hypothyroidism may result at any age if the dietary intake of iodine is extremely low. Several other forms of hypothyroidism that have a genetic or familial basis also exist. Although enlargement of the thyroid gland (goiter) is usually associated with hyperthyroidism, goiter may also be present in some forms of hypothyroidism, albeit for different reasons. For instance, thyroid enlargement occurs during hypothyroidism when there is a lack of dietary iodine (endemic goiter). But thyroid hormone synthesis is incomplete, because no iodine is available to add to the tyrosine residues. Consequently, the thyroid gland increases in size because of the unabated production of thyroglobulin. Replacement of deficient thyroid hormones is essential for maintaining optimal health in adults with various forms of hypothyroidism. There has been considerable debate about whether a replacement regimen should consist of T4 only or a combination of T4 and T3. Some studies suggested that combining both hormones does not provide additional benefits in certain physiological responses. Administration of thyroid hormones is likewise important in infants and children with hypothyroidism because adequate amounts of these hormones are needed for normal physical and mental development. Physicians may administer thyroid hormones to prevent and treat cancer of the thyroid gland and to prevent enlargement of the thyroid gland (goiter) caused by other drugs, such as lithium. Thyroid hormone maintenance may be beneficial in patients who are in the preliminary or subclinical phase of hypothyroidism. Some clinicians feel that administering these hormones in the early stages may prevent the disease from fully developing. Long-term administration of the hormones is usually a safe, effective means of maintaining optimal patient health. Symptoms of excess drug levels are similar to the symptoms of hyperthyroidism (see Table 31-2). Despite their diminutive size, parathyroids serve a vital role in controlling calcium homeostasis. In fact, removal of the parathyroid glands results in convulsions and death because of inadequate plasma calcium levels. How these hormones interact in controlling normal bone formation and resorption is of particular interest to rehabilitation specialists. The following section presents the regulation of bone mineral homeostasis and the principal hormones involved in this process. The primary minerals that enable bone to maintain its rigidity are calcium and phosphate. Excessive release of these minerals from storage sites in bone will result in bone demineralization, and the skeletal system will undergo failure. In addition, bone is continually undergoing specific changes in its internal architecture. This process of remodeling allows bone to adapt to changing stresses and optimally resist applied loads. The balance between bone resorption and formation is controlled by the complex interaction of local and systemic factors. In particular, several hormones regulate bone formation and help maintain adequate plasma calcium levels. The role of parathyroid hormone, vitamin D, and calcitonin in regulating bone mineral homeostasis is described below. Vitamin D Vitamin D produces several metabolites that are important in bone mineral homeostasis. Under normal conditions, vitamin D generally enhances bone formation by increasing the supply of the two primary minerals needed for bone formation (calcium and phosphate). Hence, vitamin D usually favors increased bone mineralization, but this effect may be reversed to help resolve a deficiency of plasma calcium. These calcitonin-secreting cells (also known as parafollicular or C cells) are interspersed between follicles that produce thyroid hormones. Renal excretion of calcium and phosphate is increased by a direct effect of calcitonin on the kidneys, which further reduces the levels of these minerals in the bloodstream. Calcitonin does have an important therapeutic function, and pharmacological doses of calcitonin may be helpful in preventing bone loss in certain conditions (see "Pharmacological Control of Bone Mineral Homeostasis"). Blood calcium levels must be maintained within a limited range to ensure an adequate supply of free calcium for various physiological purposes. Excess plasma calcium (blood levels greater than 12 mg/100 mL) depresses nervous function, leading to sluggishness, lethargy, and possibly coma. Chronic disturbances in calcium homeostasis can also produce problems in bone calcification. Likewise, various metabolic bone diseases and problems in bone metabolism can alter blood calcium levels, leading to hypocalcemia or hypercalcemia. Some of the more common metabolic diseases affecting bone mineralization are listed in Table 31-4. Consequently, patients often must use pharmacological methods to help control bone mineral levels in their bloodstream and maintain adequate bone mineralization. The following sections discuss the specific drugs used to control bone mineralization and the clinical conditions in which they are used. On the other hand, glucocorticoids produce a catabolic effect on bone and other supporting tissues (see Chapter 29). In addition, disturbances in any of these secondary endocrine systems may produce problems that are manifested in abnormal bone formation, including excess glucocorticoid activity and growth hormone deficiency. Specifically, the patients may use calcium supplements to help prevent bone loss in conditions such as osteoporosis, osteomalacia, rickets, and hypoparathyroidism (see Table 31-5). Calcium supplements, for example, are recommended in preventing and treating osteoporosis in postmenopausal women. The exact dose for a patient therefore depends on factors such as the amount of dietary calcium, age, gender, and hormonal and reproductive status. Certain guidelines, for example, suggest that no more than 500 mg of calcium should be administered at one time77 and that daily calcium doses used to prevent fractures in adults should be limited to 1,000 mg/day or less in divided doses. In addition to concerns about cardiovascular disease, excessive calcium doses may also produce symptoms of hypercalcemia, including constipation, drowsiness, fatigue, and headache. As hypercalcemia becomes more pronounced, confusion, irritability, cardiac arrhythmias, hypertension, nausea and vomiting, skin rashes, and pain in bones and muscle may occur. Hypercalcemia is a cause for concern because severe cardiac irregularities may prove fatal. Vitamin D As indicated earlier, vitamin D is a precursor for several compounds that tend to promote bone mineralization, primarily by increasing intestinal absorption of calcium and phosphate. Vitamin D analogs such as calcitriol can be combined with calcium supplements to help treat postmenopausal osteoporosis75 and to treat bone loss caused by anti-inflammatory steroids (glucocorticoids; see Chapter 29). Currently, the recommended daily intake of vitamin D is 400 units in infants up to 1 year, 600 units in children and adults up to age 70, and 800 units in adults over age 70.