David Ashley, MBBS, PhD

• Professor of Neurosurgery
• Rory David Deutsch Distinguished Professor of Neuro-Oncology
• Professor of Medicine
• Professor in Pediatrics
• Professor in Pathology
• Member of the Duke Cancer Institute

https://medicine.duke.edu/faculty/david-ashley-mbbs-phd

When cast nephropathy is present on biopsy heart attack 50 years order generic furosemide on line, a course of plasmapheresis in conjunction with treatment of the myeloma may stabilize renal function arrhythmia what to do discount furosemide uk. There is no specific treatment for fibrillary or immunotactoid glomerulopathy arrhythmia update 2010 cheap furosemide 100 mg on line, although addressing an underlying malignancy hypertension hypokalemia purchase generic furosemide line, if present hypertension kidney disease cheap 100 mg furosemide with visa, may slow progression in the latter. However, as the molecular basis for disease is elucidated, an alternate classification has been proposed (N Engl J Med 2012;366:1119). Deficiencies of or antibodies against the complement regulators (factors H and I) may also activate the complement cascade. If renal function is rapidly deteriorating in the presence of cryoglobulins, plasmapheresis may help stabilize disease. Presentation is most commonly in the second or third decade of life, generally following a slowly progressive course. Henoch-Schönlein purpura is a related disorder that may represent a systemic form of the same disease, with vasculitic involvement of the skin (palpable purpura of the lower trunk and extremities), gastrointestinal tract, and joints. Abnormally glycosylated IgA is thought to be responsible for immune complex formation and mesangial deposition. Although serum IgA levels do not correlate with disease activity, events that potentially lead to overproduction (concurrent upper respiratory infection) or decreased clearance (hepatic cirrhosis) may predispose to disease. Progressive disease may benefit from a course of prednisone 1 mg/kg/d with or without cytotoxic agents. It is classically associated with streptococcal infection, which typically affects children under the age of 10 years, after a latent period of 2-4 weeks from onset of pharyngitis or skin infection. However, bacterial endocarditis, visceral abscesses, and ventriculoperitoneal shunt infections can also lead to this immune complex-mediated disease. There is widespread mesangial proliferation as well as an infiltration of polymorphonuclear cells. Resolution of the underlying infection typically leads to renal recovery in 2-4 weeks, even in cases where dialytic support was needed. The World Health Organization classification has five major categories based on histologic appearance. Immunofluorescence is usually positive for IgG, IgA, IgM, C1q, C3, and C4, for the "full-house" fluorescence pattern. Remission can be maintained for several years with mycophenolate mofetil 1000 mg twice daily, which was shown to be superior to azathioprine 2 mg/kg/d in preventing relapse (N Engl J Med 2011;365:1886). Typically, this results in rapidly progressive renal failure often with concurrent pulmonary involvement in the form of alveolar hemorrhage. Goodpasture syndrome includes pulmonary involvement and can present with life-threatening alveolar hemorrhage. Biopsy findings include a small-vessel vasculitis with noncaseating granuloma formation in the kidneys, lungs, or sinuses. Even if the likelihood of renal recovery is low, evidence of pulmonary involvement warrants aggressive therapy. Double-strength sulfamethoxazole-trimethoprim given twice daily has been shown to reduce extrarenal relapses and to prevent Pneumocystis (carinii) jirovecii infection in patients on high-dose immunosuppression. The polycystin gene products primarily localize to the cilia of the tubular apical membrane. Disordered regulation of cell division may lead to overgrowth of the tubular segment, eventually pinching off from the rest of the collecting system. As the affected tubules enlarge, they impinge upon the blood flow to neighboring glomeruli, rendering them ischemic. This is turn activates the renin-angiotensinaldosterone system, leading to systemic hypertension. Flank pain may also be caused by cyst infection or stretching of the renal capsule. Diagnostic Testing Differentiation from other cystic diseases (acquired cystic disease, medullary sponge kidney, medullary cystic kidney disease) can be made by the presence of enlarged cystic kidneys rather than shrunken or normal-sized cystic kidneys. For patients age 60 years and older, the diagnosis requires at least four cysts in each kidney. Genetic testing may be considered if patients have equivocal imaging results or if a definitive diagnosis is required. Gross hematuria from cyst hemorrhage can usually be managed with bed rest, hydration, and analgesia. Cyst infections are generally treated with antibiotics that achieve good penetration into the cysts. The absence of bacterial growth in the urine does not rule out infection because the cystic fluid does not necessarily communicate with the rest of the collecting system. Pain that persists without an obvious hemorrhagic or infectious cause may respond to cyst reduction surgery, particularly if there is a culprit cyst that can be identified and targeted. As the underlying mechanism for cyst growth is clarified, newer treatment options are emerging. Past trials investigating the antimetabolites sirolimus and everolimus have been disappointing. Calcium phosphate stones can appear as elongated, blunt crystals and form in alkaline urine. Calcium oxalate stones can be found in acidic or alkaline urine and can be dumbbell shaped or appear as paired pyramids (giving them an envelope appearance when viewed on end). Uric acid stones can be idiopathic or develop as part of hyperuricosuric states such as gout and myeloproliferative disorders. Uric acid crystals exhibit a variety of shapes, with needles and rhomboid forms being the most common. Struvite stones contain magnesium, ammonium, and phosphate, and develop in alkaline urine associated with urea-splitting organisms. They are radiopaque and can extend to fill the renal pelvis, taking on a staghorn configuration. Cystine stones are uncommon and can form as the result of an autosomal recessive disorder. These stones have an intermediate radiolucency and appear as hexagonal crystals in the urine. Diagnostic Testing Basic laboratory investigation should include urine culture, pH, microscopy, and serum calcium, phosphate, parathyroid hormone, and uric acid levels. Recurrent stone formers should undergo a more extensive evaluation, with 24-hour urine collections for calcium, phosphate, uric acid, citrate, oxalate, and cystine. This collection should not be done during an acute episode in a hospitalized patient but rather reserved for when the patient is on his or her usual outpatient diet. If the stone is obstructing outflow or is accompanied by infection, removal is indicated with urgent urologic or radiologic intervention. After passage of a stone, treatment is directed at prevention of recurrent stone formation. Regardless of stone type, the foundation of therapy is maintenance of high urine output (2-3 L/d) with oral hydration and a low-sodium diet (<2 g/d). For calcium oxalate stones, a low-calcium diet is no longer recommended given the risks of osteoporosis. Instead, patients should be on a normal-calcium diet with no added calcium supplements. Thiazide diuretics may reduce calciuria, and potassium citrate may be added in patients with hypocitraturia. Uric acid stones can be prevented or reduced in size by allopurinol or urinary alkalinization with citrate, bicarbonate, or acetazolamide. Monthly urine cultures should be obtained, and if positive, aggressive antibiotic treatment is indicated. Dpenicillamine and mercaptopropionylglycine can further increase solubility through breakage and exchange of disulfide bonds. Side effects of D-penicillamine and mercaptopropionylglycine include fever, rash, arthritis, myelosuppression, hepatotoxicity, and vitamin B6 deficiency. To be classified as stage 1 or stage 2, there must be an accompanying structural or functional defect. Patients are usually asymptomatic until significant renal function is lost (late stage 4 and stage 5). This can be useful in end-stage planning and in predicting when renal replacement therapy will be needed. This can occur with true volume depletion or diminished effective circulating volume. Uncontrolled hypertension leads to hyperfiltration, which may lead to worsening proteinuria and further damage to the glomeruli. Albuminuria has also been identified as a risk factor for progression of renal disease. Nephrotoxic agents, such as iodinated contrast agents and aminoglycosides, should be avoided when possible. Contrast nephropathy and atheroembolic disease are potential complications, and the risks and benefits of the procedure must be weighed with the patient prior to proceeding. Restriction to <2 g/d should be used if heart failure or refractory hypertension is present. Tomato-based products, bananas, potatoes, and citrus drinks are high in potassium and should be avoided in these patients. Oral binders (calcium carbonate or acetate, lanthanum carbonate, sevelamer carbonate) can be used if dietary restrictions are unable to control phosphate levels. Hypertension Uncontrolled hypertension accelerates the rate of decline of renal function. They lower intraglomerular pressure and possess renoprotective properties beyond the antihypertensive effect, particularly in proteinuric states. Due to their effects on intrarenal hemodynamics, a 30% rise in serum Cr should be anticipated and tolerated; a further rise should prompt a search for possible renal artery stenosis. The Cr and serum potassium should be checked approximately 1-2 weeks after a dose adjustment. Alternate causes for an anemia should be entertained in the appropriate setting and iron stores assessed. The minimum dose that maintains the hemoglobin above the need for transfusion and below 11 g/dL should be used. Osteitis fibrosa cystica is commonly associated with secondary hyperparathyroidism and increased bone turnover, resulting in bone pain and fractures. Osteomalacia can involve deposition of aluminum into bone and is less commonly seen today with the decreased use of aluminum-based phosphate binders. The duration of treatment depends on severity of the deficiency, with levels <5 ng/dL warranting at least 12 weeks of treatment. Calcium-based binders are effective when given with meals as calcium carbonate (200 mg of elemental calcium per 500-mg tablet) or calcium acetate (169 mg of elemental calcium per 667-mg tablet). Calcium levels need to be monitored regularly and doses adjusted to avoid hypercalcemia. It should be used only in dialysis patients and usually in conjunction with active vitamin D, because it may induce significant hypocalcemia and is relatively ineffective as monotherapy. As renal function deteriorates, the kidney is unable to appropriately excrete sufficient acid, resulting in metabolic acidosis (mixed high and normal anion gap). Treatment with sodium bicarbonate 650-1300 mg thrice daily can help maintain the serum bicarbonate level at 22 mEq/L. Such therapy, however, can increase the sodium load and contribute to edema or hypertension. Common acute indications include hyperkalemia, metabolic acidosis, and volume overload that are refractory to medical management. Uremic encephalopathy or pericarditis, as well as certain intoxications (methanol, ethylene glycol, or salicylates), can all be indications to initiate dialytic therapy acutely. In the chronic setting, renal replacement therapy is typically begun prior to the worsening of the metabolic or nutritional status of the patient. Dialysis works by solute diffusion and water transport across a selectively permeable membrane. In hemodialysis, blood is pumped counter-currently to a dialysis solution within an extracorporeal membrane. This can be performed intermittently (3-4 hours during the day) or in a continuous 24-hour fashion depending on hemodynamic stability or goals of therapy. Transplantation offers the best long-term survival and most completely replaces the filtrative and endocrine functions of the native kidney. Diffusion the selectively permeable membrane contains pores that allow electrolytes and other small molecules to pass by diffusion while holding back larger molecules and cellular components of the blood. Movement relies on the molecular size and the concentration gradient, where Cr, urea, potassium, and other waste products of metabolism pass into the dialysis solution while alkaline buffers (bicarbonate or lactate) enter the blood from the dialysis solution. It can be achieved in hemodialysis via a transmembrane hydrostatic pressure that removes excess fluid from the blood compartment. This usually accounts for only a small fraction of the total clearance but can be significantly increased if a physiologic "replacement fluid" is infused into the patient concurrently to prevent hypovolemia. This strategy is frequently employed by continuous hemodialysis modalities (see the following text). The slower blood flows usually necessitate anticoagulation (with systemic heparin or regional citrate) to prevent the filter from clotting. Intermediate blood flows lower the clotting risk if anticoagulation is not used, while intermediate treatment lengths (8-10 hours) still allow for adequate clearances. Patients also spend a significant portion of the day off the machine to allow for nonbedside testing, procedures, and physical therapy. In the acute setting, the appropriate interval is not clearly known, although a thrice-weekly schedule is likely adequate; daily assessment should be performed to reevaluate dialytic needs. One must be vigilant in checking electrolyte levels (particularly ionized calcium and phosphorus) to ensure they remain within the desired ranges. Calcium levels are especially important to follow when regional citrate anticoagulation is being used. They are almost exclusively used in the inpatient setting and are generally used for 1-2 weeks.

Secondary granules also fuse with the phagosomes blood pressure ranges pediatrics discount 100 mg furosemide visa, and new enzymes from these granules including lactoferrin attack the organism blood pressure viagra furosemide 100 mg purchase amex. Various types of activated oxygen hypertension canada 40 mg furosemide buy fast delivery, generated by glucose metabolism blood pressure medication toprol 40 mg furosemide purchase visa, also help to kill bacteria blood pressure medication used in pregnancy order furosemide without a prescription. Chapter 8: White cells: granulocytes and monocytes / 93 physiological conditions; inflammatory chemokines are induced or upregulated by inflammatory stimuli. They bind to and acti vate cells via chemokine receptors and play an important part in recruiting appropriate cells to the sites of inflammation. Killing and digestion this occurs by oxygendependent and oxygenindependent pathways. In neutrophils, H2O2 reacts with myeloperoxidase and intracellular halide to kill bacteria; activated oxygen may also be involved. They may also act with a fall in pH within phagocytic vacu oles into which lysosomal enzymes are released. Lactoferrin, an ironbinding protein, is bacteriostatic by depriving bacteria of iron and generating free radicals. Defects of phagocytic cell function Chemotaxis these defects occur in rare congenital abnormalities. Phagocytosis these defects usually arise because of a lack of opsonization which may be caused by congenital or acquired causes of hypo gammaglobulinaemia or lack of complement components. Killing this abnormality is clearly illustrated by the rare Xlinked or autosomal recessive chronic granulomatous disease that results from abnormal leucocyte oxidative metabolism. There is an abnormality affecting different elements of the respiratory burst oxidase or its activating mechanism. The patients have recurring infections, usually bacterial but sometimes fungal, which present in infancy or early childhood. Other rare congenital abnormalities may also result in defects of bacterial killing. Acute or chronic myeloid leukaemia and myelodysplastic syndromes may also be associated with defective killing of ingested microorganisms. Benign disorders A number of the hereditary conditions may give rise to changes in granulocyte morphology. Other rare disorders In contrast to these two benign anomalies, other rare congenital leucocyte disorders may be associated with severe disease. The Chédiak­Higashi syndrome is inherited in an autosomal reces sive manner, and there are giant granules in the neutrophils, eosinophils, monocytes and lymphocytes, accompanied by neutropenia, thrombocytopenia and marked hepatosplenom egaly. Abnormal leucocyte granulation or vacuolation is also seen in patients with rare mucopolysaccharide disorders. Hypersegmented forms occur in megaloblastic anaemia, Döhle bodies and toxic changes in infection. Pelger cells, seen in the benign congenital abnormality, also occur in patients with acute myeloid leukae mia or myelodysplasia. Bacterial infections (especially pyogenic bacterial, localized or generalized) Inflammation and tissue necrosis. Associated disorders include severe or chronic infec tions, severe haemolysis or metastatic cancer. Leucoerythroblastic reaction this is characterised by the presense of erythroblast and granu locyte precursors in the blood. Neutrophil leucocytosis is sometimes accompanied by fever as a result of the release of leucocyte pyrogens. The leukaemoid reaction the leukaemoid reaction is a reactive and excessive leucocytosis usually characterized by the presence of immature cells. This shows an erythroblast, promyelocyte, myelocyte and metamyelocytes in a patient with metastatic breast carcinoma in the bone marrow. Metastatic neoplasm in the marrow Primary myelofibrosis Acute and chronic myeloid leukaemia Myeloma, lymphoma Miliary tuberculosis Severe megaloblastic anaemia Severe haemolysis Osteopetrosis Table 8. Benign ethnic neutropenia Black people often have a low neutrophil count which is termed benign ethnic neutropenia. The reduction in the neutrophil count may result from increased neutrophil margination, but there are no significant clinical consequences. Other types are autosomally recessive, or the neutro penia occurs as part of other syndromes. Idiopathic benign neutropenia An increase in the marginating fraction of blood neutrophils and a corresponding reduction in the circulating fraction is one cause of benign neutropenia. The term chronic idiopathic neutropenia is used for unex plained acquired neutropenia (neutrophil count below normal for the ethnic group), without phasic variations or underly ing disease. It is more common in females and thought to be brought about by immune cells causing inhibition of myelo poiesis in the bone marrow. Clinical features Severe neutropenia is particularly associated with infections of the mouth and throat. Organisms carried as com mensals by normal individuals, such as Staphylococcus epidermidis or Gramnegative organisms in the bowel, may become pathogens. Other features of infections associated with severe neutropenia are described on p. Diagnosis Bone marrow examination is useful in determining the severity of damage in granulopoiesis. Marrow aspiration and trephine biopsy may also provide evidence of leukaemia, myelodysplasia or other infiltration. Management the treatment of patients with acute severe neutropenia is described on p. In many patients with druginduced neutropenia, spontaneous recovery occurs within 1­2 weeks after stopping the drug. Patients with chronic neutropenia have recurrent infections which are mainly bacterial in origin, although fungal and viral infections (especially herpes) also occur. Early recognition and vigorous treatment with anti biotics, antifungal or antiviral agents, as appropriate, is essential. Corticosteroid therapy or splenectomy has been associated with good results in some patients with autoimmune neutropenia. Corticos teroids impair neutrophil function and should not be used indiscriminately in patients with neutropenia. Causes of monocytosis, eosinophil and basophil leucocytosis Monocytosis A rise in blood monocyte count above 0. Eosinophilic leucocytosis (eosinophilia) the causes of an increase in blood eosinophils. It is most frequently due to allergic diseases, parasites, skin diseases or drugs. Sometimes no underlying cause is found, no clonal marker can be detected and if the eosinophil count is elevated (above 1. In this the heart valves, central nervous system, skin and lungs may be affected; treatment is usually with steroids or cytotoxic drugs. Loefflers syndrome is a transient reactive form affecting the lungs and the Churg­ Strauss syndrome consists of a vasculitis with eosinophilic granulomas affecting the respiratory tract. In other cases of chronic eosinophilia, often with similar clinical features, a clonal cytogenetic or molecular abnormality is present and the term chronic eosinophilic leukaemia is diagnosed (see p. The usual cause is a myeloproliferative disorder such as chronic myeloid leukaemia or polycythaemia vera. Reactive basophil increases are sometimes seen in myxoedema, during smallpox or chickenpox infection and in ulcerative colitis. Histiocytic and dendritic cell disorders Histiocytes are myeloidderived tissue macrophages. Dendritic cells these are specialized antigenpresenting cells found mainly in the skin, lymph nodes, spleen and thymus. The primary role of dendritic cells is antigen presentation to T and B lymphocytes (p. There is a clonal proliferation of myeloid derived cells resembling antigen presenting cells of the skin. The multisystem disease affects children in the first 3 years of life with hepatosplenomegaly, lymphadenopathy and ecze matous skin symptoms. Localized lesions may occur, espe cially in the skull, ribs and long bones, the posterior pitui tary causing diabetes insipidus, the central nervous system, gastrointestinal tract and lungs. Haemophagocytic lymphohistiocytosis (haemophagocytic syndrome) this is a rare, recessively inherited or more frequently acquired disease, usually precipitated by a viral (especially Epstein­ Barr), bacterial or fungal infection or occurring in asso ciation with immunosuppression or tumours. In the familial form, various genes, such as perforin, have been shown to be mutated. Patients present with fever and pancytopenia, often with splenomegaly and liver dysfunction. There are increased numbers of histiocytes in the bone marrow which ingest red cells, white cells and platelets. Chapter 8: White cells: granulocytes and monocytes / 99 Sinus histiocytosis with massive lymphadenopathy this is also known as the Rosai­Dorfman syndrome. Malignant diseases of histiocytic or dendritic cells include sarcomas, chronic myelomonocytic leukaemia (see Chapter 16) and a rare type of acute myeloid leukaemia (see Chapter 13). Type I is caused by a variety of mutations in the glucocerebrosidase gene, one type of which (a single base pair substitution in codon 444) is particularly common in Ashkenazi Jews and explains the high incidence of the disease in this group. Moderate liver enlargement and pingueculae (conjunctival deposits) are other characteristics. This is due to thrombocyto penia with abnormal platelet function and coagulation defects. The clinical manifestations are caused by the accumulation of glucocerebrosideladen macrophages in the spleen, liver and bone marrow. Gaucher cells are not inert lipid storage containers but are metabolically active, secreting proteins that cause secondary pathology. Polyclonal hypergammaglobulinaemia or monoclonal gammopathy are frequent with a risk of myeloma. Lysosomal enyzmes, chitotriosidase and acid phosphatase are raised and useful in monitoring therapy. Enzyme replacement therapy with glucocerebrosidase as imiglucerase (Cerezyme), velaglucerase or taliglucerase, made by recombinant technology and given intravenously once every 2 weeks, is effective in treating the disease with shrink age of spleen, rise in blood count and improved bone structure. Oral drugs, miglustat or eliglustat, are useful alone in mild forms or in combination with the intravenous enzyme. The use of enzyme replacement has virtually eliminated the need for splenectomy but it cannot reverse established osteonecrosis, bone deformation, hepatic, splenic or marrow fibrosis. The majority of patients are infants who die in the first few years of life, although occasional patients survive to adult life. Massive hepatosplenomegaly occurs and there is usually lung and nervous system involvement with retarded physical and mental development. Chemical analysis of the tissues reveals that the disorder is caused by an accumulation of sphin gomyelin and cholesterol. Chitotrisidase 3 (nmol/hr/mL x 10) Chapter 8: White cells: granulocytes and monocytes / 101 Granulocytes include neutrophils (polymorphs), Defects of function of neutrophils and monocytes may eosinophils and basophils. They are made in the bone marrow under the control of a variety of growth factors and have a short lifespan in the blood stream before entering tissues. Neutrophil leucocytosis occurs in bacterial infection and in other types of inflammation. It may be caused by bone marrow failure, chemotherapy or radiotherapy drugs, immune mechanisms or occur congenitally. Eosinophilia is most frequently caused by allergic diseases, including skin diseases, parasitic infections or drugs. It can be caused by a clonal increase in eosinophils, termed chronic eosinophilic leukaemia, or an idiopathic condition, often associated with tissue damage. The haemophagocytic syndrome involves destruction of red cells, granulocytes and platelets by tissue macrophages. Lysosomal storage diseases are caused by inherited defects in the enzymes responsible for breakdown of glycolipids. Treatment is with enzyme replacement or substrate reduction therapy Now visit Lymphocytes are the immunologically competent cells that assist phagocytes in defence of the body against infection and other foreign invasion. Two unique features char acteristic of the immune system are the ability to generate antigenic specificity and the phenomenon of immunological memory. A complete description of the functions of lym phocytes is beyond the scope of this book, but information essential to an understanding of the diseases of the lymphoid system, and of the role of lymphocytes in other haematological diseases, is included here. Lymphocytes In postnatal life, the bone marrow and thymus are the primary lymphoid organs in which lymphocytes develop. The secondary lymphoid organs in which specific immune responses are generated are the lymph nodes, spleen and lym phoid tissues of the alimentary and respiratory tracts. B and T lymphocytes the immune response depends upon two types of lymphocytes, B and T cells (Table 9. B cells mature in the bone marrow and circulate in the peripheral blood until they undergo recognition of antigen. T cells develop from cells that have migrated to the thymus where they differentiate into mature T cells during passage from the cortex to the medulla. The cells also express one of two Tcell antigen receptor heterodim ers, ab (>90%) or gd (<10%). Two antigenbinding chains (a, b) are associated with several proteins (g, d, e, z) that mediate signal transduction. Lymphocyte circulation Lymphocytes in the peripheral blood migrate through post capillary venules into the substance of the lymph nodes or into the spleen or bone marrow. T cells home to the perifol licular zones of the cortical areas of lymph nodes (paracortical areas). Lymphocytes return to the peripheral blood via the efferent lymphatic stream and the thoracic duct. They are divided into five subclasses or isotypes: immunoglobulin G (IgG), IgA, IgM, IgD and IgE. IgG, the most common, contributes approxi mately 80% of normal serum immunoglobulin and is further subdivided into four subclasses: IgG1, IgG2, IgG3 and IgG4.

This also includes determining whether an individual lesion lasts >24 hours blood pressure lowering discount furosemide 40 mg buy on-line, in which case the diagnosis of urticarial vasculitis must be investigated by a skin biopsy blood pressure pump cheap furosemide online. Any changes in environmental exposures blood pressure medication for nightmares cheap furosemide online american express, foods blood pressure up and down causes discount furosemide on line, medications heart attack demi lovato sam tsui chrissy costanza of atc buy furosemide from india, personal care products, etc. It is important to differentiate from anaphylaxis, which affects organs other than the skin, as this will be treated differently (see Anaphylaxis section). Angioedema appears as swelling; can often involve the face, tongue, extremities, or genitalia; and may be asymmetric. Differential Diagnosis IgE-mediated allergic reaction to drugs, foods, insects, inhalant, or contact allergen. Diagnostic Testing Epicutaneous skin testing and patch testing are only indicated when symptoms are associated with specific triggers. Laboratories Routine laboratory testing in the absence of a clinical history is rarely helpful in determining an etiology in chronic urticaria. Autologous serum skin testing, assays for basophil histamine release, and autoantibodies to IgE and the high-affinity IgE receptor are available, but the utility of these tests has not been established. Diagnostic Procedures A skin biopsy should be performed if individual lesions persist for >24 hours to rule out urticarial vasculitis. Biopsy of acute urticarial lesions reveals dilation of small venules and capillaries located in the superficial dermis with widening of the dermal papillae, flattening of the rete pegs, and swelling of collagen fibers. Chronic urticaria is characterized by a dense, nonnecrotizing, perivascular infiltrate consisting of T lymphocytes, mast cells, eosinophils, basophils, and neutrophils. Angioedema shows similar pathologic alterations in the deep, rather than superficial, dermis, and subcutaneous tissue. In some instances, it is possible to reintroduce an agent cautiously if it is believed not to be the etiologic agent. This trial should be done in the presence of a physician with epinephrine readily available. Careful consideration should be given to the elimination or substitution of each prescription or over-the-counter medication or supplement. If a patient reacts to one medication in a class, the reaction likely will be triggered by all medications in that class. In patients presenting with hereditary and acquired angioedema, a prompt assessment of airway is critical, especially in those presenting with a laryngeal attack. Medications If acute urticaria is associated with additional systemic symptoms such as hypotension, laryngeal edema, or bronchospasm, treatment with epinephrine (0. First Line Acute urticaria and/or angioedema Second-generation antihistamines such as cetirizine, fexofenadine, or loratadine should be administered to patients until the hives have cleared. A first-generation antihistamine such as hydroxyzine may be added as an evening dose if needed to obtain control in refractory cases. Oral corticosteroids should be reserved for patients with moderate to severe symptoms. If a patient presents with systemic symptoms, self-administered epinephrine should be prescribed for use in the case of anaphylaxis. Chronic urticaria A stepwise approach has been suggested for the treatment of chronic urticaria (J Allergy Clin Immunol 2014;133(5):1270). Omalizumab: Proven safe and effective in several randomized clinical trials in patients with chronic urticaria not responsive to standard dose of H1 antihistamines Cyclosporine Other anti-inflammatory agents, immunosuppressants, or biologics Optimal duration of therapy has not been established; tapering medications after 3-6 months of symptom control has been suggested. Hereditary and acquired angioedema (disorder of C1 inhibitor) Laryngeal attacks or severe abdominal attacks: C1 inhibitor concentrate, icatibant, and ecallantide are first-line agents. Secondary immunodeficiencies are also disorders of increased susceptibility to infection but are attributable to an external source. Predominantly antibody deficiencies: the defect is primarily in the ability to make antibodies. Diseases of immune dysregulation: Autoimmunity and lymphoproliferation are characteristic manifestations in these disorders. Etiology Predominantly antibody immune deficiencies are thought to be caused by defects in B-cell maturation. Combined immunodeficiencies are caused by defective T-cell-mediated immunity and associated antibody deficiency. Secondary immunodeficiencies can be caused by medications (chemotherapy, immunomodulatory agents, corticosteroids), infectious agents. Clinical suspicion should be increased by recurrent sinopulmonary infection, deep-seated infections, opportunistic infections, or disseminated infections in an otherwise healthy patient. Selective IgA deficiency is the most common immune deficiency, with a prevalence of 1 in 300-500 people. Therapy is directed at early treatment with antibiotics because IgA replacement is not available. It includes a heterogeneous group of disorders in which most patients present in the second to fourth decade of life with recurrent sinus and pulmonary infections and are discovered to have low and dysfunctional IgG, IgA, and/or IgM antibodies with poor response to immunizations. B-cell numbers are often normal, but there is decreased ability to produce immunoglobulin due to the lack of isotype-switched memory B cells. Patients may have associated gastrointestinal disease or autoimmune abnormalities (most commonly autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, pernicious anemia, and rheumatoid arthritis). There is an increased incidence of malignancy, especially lymphoid and gastrointestinal malignancy. Specific antibody deficiency is defined as poor or absent antibody responses to polysaccharide antigens. Therapeutic approaches include adequate antibiotic treatment for infections, pneumococcal conjugate vaccine, and sometimes immunoglobulin replacement. Patients usually have low levels of all immunoglobulin types and very low levels of B cells. Specific genetic defect is in Bruton tyrosine kinase, which is involved in B-cell maturation. Deficiencies of each of the IgG subclasses (IgG1, IgG2, IgG3, and IgG4) have been described. Isolated subclass deficiency without recurrent infections is of unknown clinical significance. Hyper-IgE syndrome (Job syndrome) is characterized by recurrent pyogenic infections of the skin and lower respiratory tract. The most common organism involved is Staphylococcus aureus, but other bacteria and fungi have been reported. Patients present with recurrent infections and have associated pruritic dermatitis, coarse (lion-like) facies, growth retardation, scoliosis, retention of primary teeth, and hyperkeratotic nails. Laboratory data reveal the presence of normal levels of IgG, IgA, and IgM but markedly elevated levels of IgE. Recurrent disseminated neisserial infections are associated with a deficiency in the terminal complement system (C5-C9). Systemic lupus-like disorders and recurrent infection with encapsulated organisms have been associated with deficiencies in other components of complement. Diagnosis is made by demonstration of defective respiratory burst with flow cytometry assay using dihydrorhodamine. Characteristic infections include mycobacterial infections (including typical and atypical Mycobacterium) and Salmonella infections. Initial evaluation should focus on identifying possible secondary causes of recurrent infection such as allergy, medications, and anatomic abnormalities. Other specialized tests including genetic testing may be needed to make a definitive diagnosis. Titers of specific antibodies are measured before and at 4-8 weeks after immunization. However, these patients should be promptly treated at the first sign of infection with an antibiotic that covers Streptococcus pneumoniae or Haemophilus influenzae. Numerous preparations of immunoglobulin are available, all of which undergo viral inactivation steps. Possible side effects include myalgias, vomiting, chills, and lingering headache (due to immune complexmediated aseptic meningitis). Because the majority of water is contained in the intracellular space, the loss of water alone (without Na+) does not typically result in the hemodynamic changes associated with volume depletion. Although vasopressin release is predominately responsive to osmotic cues, volume contraction can cause a nonosmotic release of vasopressin, resulting in a reduction of renal water excretion. Clinically, this manifests as volume depletion (hypotension, tachycardia) and volume expansion (peripheral or pulmonary edema). Na+ concentration reflects the amount of Na+ distributed in a fixed quantity of water. This response is mediated by cardiovascular, renal, hepatic, and central nervous system sensors of the effective circulating volume. The Euvolemic Patient In a euvolemic patient, the goal of fluid and electrolyte administration is to maintain homeostasis. Patient weight, which may indicate net fluid balance, should be monitored carefully. Minimum water requirements for daily fluid balance can be approximated from the sum of the required urine output, stool water loss, and insensible losses. The minimum urine output necessary to excrete the daily solute load is the amount of solute consumed each day (roughly 600-800 mOsm/d in an average individual) divided by the maximum amount of solute that can be excreted per liter of urine (maximum urine concentrating capacity is 1200 mOsm/L in healthy kidneys). Insensible water losses from the skin and respiratory tract amount to roughly 400-500 mL/d. The volume of water produced from endogenous metabolism (<250-350 mL/d) should be considered as well. The degree of insensible loss may vary tremendously depending on respiratory rate, metabolic state, and temperature (water losses increase by 100-150 mL/d for each degree of body temperature over 37°C). After adding each of these components, the minimum amount of water needed to maintain homeostasis is roughly 1400 mL/d or 60 mL/h. Electrolytes that are usually administered during maintenance fluid therapy are Na+ and K+ salts. Carbohydrate in the form of dextrose, 100-150 g/d, is given to minimize protein catabolism and prevent starvation ketoacidosis. By combining the necessary components, one can derive an appropriate maintenance fluid regimen tailored for each patient. To maintain homeostasis, you must replace 2 L of water, 154 mEq Na+, 40 mEq K+, and 100 g dextrose over the next 24 hours (values are within water and electrolyte requirements described earlier). Renal losses may be secondary to enhanced diuresis, salt-wasting nephropathies, mineralocorticoid deficiency, or resolution of obstructive renal disease. Signs of hypovolemia include low jugular venous pressure, postural hypotension, postural tachycardia, and the absence of axillary sweat. Diminished skin turgor and dry mucous membranes are poor markers of decreased interstitial fluid. Mild degrees of volume depletion are often not clinically detectable, whereas larger fluid losses can lead to mental status changes, oliguria, and hypovolemic shock. Diagnostic Testing Laboratory studies are often helpful but must be used in conjunction with the clinical picture. Urine Na+ <15 mEq is consistent with volume depletion, as is a fractional excretion of sodium (FeNa) <1%. The latter can be calculated as ([Urine Na+ × Serum Cr] ÷ [Urine Cr × Serum Na+]) × 100. Concomitant metabolic alkalosis may increase urine Na+ excretion despite volume depletion due to obligate excretion of Na+ to accompany the bicarbonate anion. In such cases, a urine chloride of <20 mEq is often helpful to confirm volume contraction. In patients with symptomatic volume depletion, a 1- to 2-L bolus is often preferable to acutely expand the intravascular space. The bolus can be repeated if necessary, although close attention should be directed toward possible signs of volume overload. Smaller boluses should be used for patients with poor cardiac reserve or significant edema. Once the patient is stable, fluids can be administered at a maintenance rate to replace ongoing losses. The Hypervolemic Patient the clinical manifestations of hypervolemia result from a surplus of total body Na+. Alternatively, it may be secondary to decreased effective circulating volume, as in heart failure, cirrhosis, or profound hypoalbuminemia. Expansion of the intravascular compartment may result in pulmonary rales, elevated jugular venous pressure, hepatojugular reflux, an S3 gallop, and elevated blood pressures. Because overt signs of hypervolemia may not manifest until 3-4 L of fluid retention, a gradual rise in water weight is often the earliest indication of Na+ retention. Diagnostic Testing Laboratory studies are generally not needed, and hypervolemia is primarily a bedside diagnosis. The urine [Na+] may be low (<15 mEq/L) with decreased effective circulating volume reflecting renal sodium retention. Alleviating the Na+ excess can be accomplished by the judicious use of diuretics and by limiting Na+ intake. Medications Diuretics enhance the renal excretion of Na+ by blocking the various sites of Na+ reabsorption along the nephron. Because of their specific site of action, thiazide diuretics impair urinary dilutional capacity (the ability to excrete water) and often stimulate a responsive increase in proximal tubule reabsorption. Loop diuretics block the Na+-K+-2Cl- transporter in the thick ascending loop of Henle. They are often used in circumstances requiring a brisk and immediate diuresis, such as acute volume overload. Loop diuretics impair urinary concentration (increase renal free water excretion) and enhance the excretion of divalent cations (Ca2+ and Mg2+).

Pathogenesis Platelet autoantibodies heart attack enzyme buy furosemide 100 mg fast delivery, usually IgG blood pressure juicing recipes 40 mg furosemide purchase with mastercard, result in the premature removal of platelets from the circulation by macrophages of the reticuloendothelial system blood pressure medication inderal purchase furosemide 40 mg line, especially the spleen blood pressure medication olmesartan furosemide 40 mg buy fast delivery. Total megakaryocyte mass and platelet turnover are increased in parallel to approximately five times normal arteria peronea purchase furosemide us. Clinical features the onset is often insidious with petechial haemorrhage, easy bruising and, in women, menorrhagia. These are orally active or given by injection and act to increase platelet production. The spleen is not palpable unless there is an associated disease causing splenomegaly. The haemoglobin concentration and white cell count are typically normal unless there is iron deficiency anaemia because of blood loss. Treatment 6 7 As this is a chronic disease the aim of treatment should be to maintain a platelet count above the level at which spontaneous bruising or bleeding occurs with the minimum of intervention. In general, a platelet count above 20 × 109/L without symptoms does not require treatment. Prednisolone 1 mg/kg/day is the usual initial therapy in adults and the dosage is gradually reduced after 10­14 days. In poor responders the dosage is reduced more slowly but alternative immunosuppression or splenectomy is considered. The mechanism of action may be blockage of Fc receptors on macrophages or modification of autoantibody production. Trials of their use as initial therapy in combination with corticosteroids are in progress. Increased reticulin and fibrosis in the bone marrow may occur with prolonged treatment but are reversible on stopping the therapy. Other treatments that may elicit a remission include danazol (an androgen which may cause virilization in women) and intravenous antiD immunoglobulin. Helicobacter pylori infection should be treated as there are some reports that this may improve the platelet count, particularly in countries where the incidence of the infection is common. Platelet transfusions Platelet concentrates are beneficial in patients with acute lifethreatening bleeding but their benefit will only last for a few hours. In approximately 75% of patients the episode follows vaccination or an infection such as chickenpox or infectious mononucleosis. Spontaneous remissions are usual but in 5­10% of cases the disease becomes chronic, lasting more than 6 months. Most children do not have any bleeding even with platelet counts <10 × 109/L but need to avoid trauma such as contact sports. If the platelet count is over 30 × 109/L no treatment is necessary unless the bleeding is severe. Indeed many doctors do not treat even with platelet counts <10 × 109/L if there is no haemorrhage. Treatment is with steroids and/or intravenous immunoglobulin, especially if there is significant bleeding. Infections It seems likely that the thrombocytopenia associated with many viral and protozoal infections is immunemediated. Druginduced immune thrombocytopenia An immunological mechanism has been demonstrated as the cause of many druginduced thrombocytopenias. Quinine (including that in tonic water), quinidine and heparin are particularly common causes (Table 25. The platelet count is often less than 10 × 109/L, and the bone marrow shows normal or increased numbers of megakaryocytes. Drugdependent antibodies against platelets may be demonstrated in the sera of some patients. The immediate treatment is to stop all suspected drugs but platelet concentrates should be given to patients with dangerous bleeding. If complement is attached and the sequence goes to completion, the platelet may be lysed directly. Otherwise it is removed by reticuloendothelial cells because of opsonization with immunoglobulin and/or the C3 component of complement. These strings are capable of embolizing to microvessels downstream and contributing to organ ischemia. The microvascular thrombosis causes variable degrees of tissue ischaemia and infarction and is responsible for the microangiopathic haemolytic anaemia and thrombocytopenia. In refractory cases and chronic relapsing cases, high dose corticosteroids, vincristine, intravenous immunoglobulin, rituximab and immunosuppressive therapy with azathioprine or cyclophosphamide have been used. Many cases are associated with Escherichia coli infection with the verotoxin 0157 strain or with other organisms, especially Shigella. Supportive renal dialysis and control of hypertension are the mainstays of treatment. Chapter 25: Bleeding disorders / 287 Disseminated intravascular coagulation In this disorder thrombocytopenia may result from a high rate of platelet destruction due to increased levels of consumption. In splenomegaly, up to 90% of platelets may be sequestered in the spleen, whereas normally this accounts for approximately onethird of the total platelet mass. Platelet lifespan is normal and, in the absence of additional haemostatic defects, the thrombocytopenia of splenomegaly is not usually associated with bleeding. Massive transfusion syndrome Platelets are unstable in blood stored at 4°C and the platelet count rapidly falls in blood stored for more than 24 hours. Patients transfused with massive amounts of stored blood, such as more than 10 units over a 24hour period, frequently show abnormal clotting and thrombocytopenia. In the more common deltastorage pool disease, there is deficiency of dense granules. Acquired disorders Antiplatelet drugs Aspirin therapy is the most common cause of defective platelet function. The cause of the aspirin defect is inhibition of cyclooxygenase with impaired thromboxane A2 synthesis. Dipyridamole inhibits platelet aggregation by blocking reuptake of adenosine and is usually used as an adjunct to aspirin. Myeloproliferative and myelodysplastic disorders Intrinsic abnormalities of platelet function occur in many patients with essential thrombocythaemia, other myeloproliferative and myelodysplastic diseases and in paroxysmal nocturnal haemoglobinuria. Hereditary disorders Rare inherited disorders may produce defects at each of the different phases of the platelet reactions leading to the formation of the haemostatic platelet plug. It usually presents in the neonatal period and, characteristically, platelets fail to aggregate in vitro to any agonist except ristocetin. Diagnosis of platelet disorders Patients with suspected platelet or blood vessel abnormalities should initially have a blood count and blood film examination. Bone marrow examination is often needed in thrombocytopenic patients to determine whether or not there is a failure of platelet production. The marrow may also reveal one of the conditions associated with defective production (Table 25. In children and young adults with isolated thrombocytopenia, the marrow test is often not performed. In the elderly, marrow examination is needed particularly to exclude myelodysplasia. Some intrinsic platelet functional disorders are associated with thrombocytopenia. The rare hereditary defects of platelet function require more elaborate in vitro tests to define the specific abnormality. Their longterm use may cause increased marrow reticulin and fibrosis which is reversible by stopping the drug. Platelet transfusions Transfusion of platelet concentrates is indicated in the following circumstances: 1 Thrombocytopenia or abnormal platelet function when bleeding or before invasive procedures and where there is no alternative therapy available. The platelet count should be above 50 × 109/L before, for example, liver biopsy or lumbar puncture. If there is infection, potential bleeding sites or coagulopathy, the count should be kept above 20 × 109/L. The indications for transfusion of platelet concentrates are discussed further on p. Thrombomimetics these are drugs that increase platelet production by activating the thrombopoietin receptor on megakaryocytes. Two such drugs are romiplostim, given subcutaneously once weekly, and eltrombopag, active orally and given daily. They may Vascular bleeding disorders may be congenital, Chronic autoimmune thrombocytopenia is treated by including hereditary haemorrhagic telangiectasia and the Ehlers­Danlos syndrome. Acquired vascular disorders include fragile capillaries in healthy women, senile purpura, purpura associated with infections, Henoch­Schönlein syndrome, scurvy and steroid therapy. It has a wide range of causes including: (i) failure of platelet production from a congenital cause, drugs or viral infection or a general bone marrow failure; (ii) increased consumption of platelets. This may be acute or chronic autoimmune, druginduced, caused by disseminated intravascular coagulation or thrombotic thrombocytopenic purpura. The platelet count may be raised by platelet transfusion or by the thrombomimetic drugs eltrombopag or romiplostim. Chapter 26: Coagulation disorders / 291 Hereditary coagulation disorders Hereditary deficiencies of each of the coagulation factors have been described. Haemophilia A Haemophilia A is the most common of the hereditary clotting factor deficiencies. Clinical features Infants may develop profuse postcircumcision haemorrhage or joint and soft tissue bleeds and excessive bruising when they start to be active. Spontaneous haematuria and gastrointestinal haemorrhage, sometimes with obstruction resulting from intramucosal bleeding, can also occur. Operative and posttraumatic haemorrhage are lifethreatening both in severely and mildly affected patients. Although not common, spontaneous intracerebral haemorrhage occurs more frequently than in the general population and is an important cause of death in patients with severe disease. Haemophilic pseudotumours are large encapsulated haematomas with progressive cystic swelling from repeated haemorrhage. They may occur in fascial and muscle planes, large muscle groups and in the long bones, pelvis and cranium. The latter result from repeated subperiosteal haemorrhages with bone destruction and new bone formation. Many patients were infected with hepatitis C virus before testing of donors and blood products became possible. The X chromosome is longer than the Y and there is nothing to pair with most of the long arm of X. The ankles and feet show residual deformities of talipes equinus, with some cavus and associated toe clawing. The scar on the medial side of the left lower thigh is the site of a previously excised pseudotumour. Coagulation factor activity (percentage of normal) <1 Treatment Most patients in developed countries attend specialized haemophilia centres where there is a multidisciplinary team dedicated to their care. Guidelines exist for the plasma level to be achieved for different types of haemorrhage. Local supportive measures used in treating haemarthroses and haematomas include resting the affected part, application of ice and the prevention of further trauma. At the earliest suggestion of bleeding, the haemophilic child may be treated at home. This advance has reduced the occurrence of crippling haemarthroses and the need for inpatient care. Severely affected patients are now reaching adult life with little or no arthritis. This may require the placement of a vascular access device such as PortaCath if venous access is difficult. A controlled trial has proven that regular prophylaxis is far superior to ondemand treatment. Haemophiliac children and their parents often require extensive help with social and psychological matters. With modern treatment the lifestyle of a haemophilic child can be almost normal but certain activities such as extreme contact sports are to be avoided, or undertaken with extra prophylaxis. Various viral vectors (retroviral, adenoassociated) as well as nonviral vectors are being explored. Immunosuppression and immune tolerance regimens have been used in an attempt to eradicate the antibody with success (at great cost) in about twothirds of cases. Indeed, the two disorders can only be distinguished by specific coagulation factor assays. Deficiency of vitamin Kdependent factors Haemorrhagic disease of the newborn Biliary obstruction Malabsorption of vitamin K. Vitamin K deficiency Fatsoluble vitamin K is obtained from green vegetables and bacterial synthesis in the gut. Deficiency may present in the newborn (haemorrhagic disease of the newborn) or in later life. Deficiency of vitamin K is caused by an inadequate diet, malabsorption or inhibition of vitamin K by vitamin K antagonist drugs such as warfarin. Gammacarboxylated glutamic acid binds calcium ions, inducing a reversible shape change in the Ntermini of vitamin K dependent proteins. Warfarin interferes with the action of vitamin K epoxide reductase leading to a functional vitamin K deficiency. Haemorrhagic disease of the newborn Vitamin Kdependent factors are low at birth and fall further in breastfed infants in the first few days of life. Liver cell immaturity, lack of gut bacterial synthesis of the vitamin and low quantities in breast milk may all contribute to a deficiency which causes haemorrhage, usually on the second to fourth day of life, but occasionally during the first 2 months. The platelet count and fibrinogen are normal with absent fibrin degradation products.

Medial Line of center of gravity is anterior to knee joint and maintains extens ion arterial dissection furosemide 40 mg buy lowest price. Imaging app Visualizing the knee joint Tibial Medial Pos terior Lateral femoral femoral collateral cruciate condyle condyle ligament ligament Femur Lateral epicondyle Lateral femoral condyle Lateral tibial condyle Head of bula Patella Medial epicondyle Medial femoral cond yle Medial tibial cond yle Intercondylar eminence Tibia Lateral femoral condyle Tibia Femur Medial femoral condyle A Medial menis cus Anterior Tibia Lateral cruciate menis cus ligament Neck of bula B Fibula C Fibula 304 blood pressure bulb replacement order furosemide without prescription. Normal knee joint showing the tibial collateral ligament heart attack neck pain purchase genuine furosemide line, the medial and lateral menisci heart attack vs cardiac arrest discount furosemide 100 mg otc, and the anterior and posterior cruciate ligaments hypertension herbs 100 mg furosemide purchase overnight delivery. The knee is exed to 90° and the heel and sole of the foot are placed on the couch. The patient is placed in a supine position and the knee is exed to approximately 90° with the foot in the neutral position. Circumflex fibular artery Recurrent branch of anterior tibial Interos s eous membrane Clinical app Arthroscopy An arthroscope is a small camera that is placed into the knee joint through the anterolateral or anteromedial aspect of the knee joint. The joint is lled with a saline solution and the camera is manipulated around the knee joint to assess the cruciate ligaments, menisci, and cartilaginous surfaces. The popliteus muscle unlocks the knee by initiating lateral rotation of the femur on the tibia. Tibio bular joint the small proximal tibio bular joint is synovial in type and allows very little movement. The opposing joint Vascular supply and innervation Vascular supply to the knee joint is predominantly through descending and genicular branches from the femoral, popliteal, and lateral circum ex femoral arteries in the thigh and the circum ex bular artery and recurrent branches from the anterior tibial artery in the leg. The knee joint is innervated by branches from the obturator, femoral, tibial, and common bular nerves. Clinical app Soft tissue injuries to the knee Soft tissue injuries are common at and around the knee joint. The typical injuries include tears of the anterior and posterior cruciate ligaments, meniscal tears, and trauma to the collateral ligaments. Isolated soft tissue injuries may occur, but it is not uncommon for certain types of injuries to occur together, for example, anterior cruciate ligament disruption, tibial collateral ligament disruption, and tears of the medial or lateral menisci. Contents the major contents of the popliteal fossa are the popliteal artery, the popliteal vein, and the tibial and common bular nerves. The tibial and common bular nerves originate proximal to the popliteal fossa as the two major branches of the sciatic nerve. They are the most super cial of the neurovascular structures in the popliteal fossa and enter the region directly from above under the margin of the biceps femoris muscle. The common bular nerve exits by following the biceps femoris tendon over the lower lateral margin of the popliteal fossa, and continues to the lateral side of the leg where it swings around the neck of the bula and enters the lateral compartment of leg. The popliteal artery is the continuation of the femoral artery in the anterior compartment of thigh, and begins as the femoral artery passes posteriorly through the adductor hiatus in the adductor magnus muscle. The popliteal artery appears deep in the popliteal fossa on the upper medial side under the margin of the semimembranosus muscle. It descends obliquely through the Popliteal fossa the popliteal fossa is an important area of transition between the thigh and leg and is the major route by which structures pass from one region to the other. The popliteal fossa is a diamond-shaped space behind the knee joint formed between muscles in the posterior compartments of thigh and leg. The margins of the smaller lower part of the space are formed medially by the medial head of the gastrocnemius muscle and laterally by the plantaris muscle and the lateral head of the gastrocnemius muscle. The oor of the fossa is formed by the capsule of the knee joint and adjacent surfaces of the femur and tibia, and, more inferiorly, by the popliteus muscle. The roof is formed by deep fascia, which is continuous above with the fascia lata of the thigh and below with deep fascia of the leg. Regional anatomy · Leg fossa with the tibial nerve and enters the posterior compartment of leg where it ends just lateral to the midline of the leg by dividing into the anterior and posterior tibial arteries. In the popliteal fossa, the popliteal artery gives rise to branches, which supply adjacent muscles, and to a series of geniculate arteries, which contribute to vascular anastomoses around the knee. It exits the popliteal fossa superiorly to become the femoral vein by passing through the adductor hiatus. The popliteal artery is the deepest of the structures in the fossa and descends through the region from the upper medial side. As a consequence of its position, the popliteal artery pulse is dif cult to nd, but usually can be detected on deep palpation just medial to the midline of the fossa. The small saphenous vein penetrates deep fascia in the upper part of the posterior leg and joins the popliteal vein. Roof of popliteal fossa the roof of the popliteal fossa is covered by super cial fascia and skin. The most important structure in the super cial fascia is the small saphenous vein. This vessel ascends vertically in the super cial fascia on the back of the leg from the lateral side of the dorsal venous arch in the foot. It ascends to the back of the knee where it penetrates deep fascia, which forms the roof of the popliteal fossa and joins with the popliteal vein. One other structure that passes through the roof of the fossa is the posterior cutaneous nerve of thigh, which descends through the thigh super cial to the hamstring muscles, passes through the roof of the popliteal fossa, and then continues inferiorly with the small saphenous vein to innervate skin on the upper half of the back of the leg. The tibia is the weight-bearing bone of the leg and is therefore much larger than the bula. The leg is divided into anterior (extensor), posterior (exor), and lateral (bular) compartments. Surface anatomy Visualizing the contents of the popliteal fossa the popliteal fossa is a diamond-shaped depression formed between the hamstrings and gastrocnemius muscle posterior to the knee. The tendons of the biceps femoris muscle and the semitendinosus muscle are palpable and often visible. The head of the bula is palpable on the lateral side of the knee and can be used as a landmark for identifying the biceps femoris tendon and the common bular nerve, which curves laterally out of the popliteal fossa and crosses the neck of the bula just inferior to the head. Muscles in the anterior compartment of leg dorsi ex the ankle, extend the toes, and invert the foot. Muscles in the posterior compartment plantar ex the ankle, ex the toes, and invert the foot. The interosseous border of the tibia is connected, by the interosseous membrane, along its length to the interosseous border of the bula. The soleal line descends across the bone from the lateral side to the medial side where it merges with the medial border. In addition, a vertical line descends down the upper part of the posterior surface from the midpoint of the soleal line. The distal end of the tibia is shaped like a rectangular box with a bony protuberance on the medial side (the medial malleolus;. The upper part of the box is continuous with the shaft of the tibia, whereas the lower surface and the medial malleolus articulate with one of the tarsal bones (talus) to form a large part of the ankle joint. The posterior surface of the boxlike distal end of the tibia is marked by a vertical groove, which continues inferiorly and medially onto the posterior surface of the medial malleolus. The lateral surface of the distal end of the tibia is occupied by a deep triangular notch (the bular notch). The bular shaft is therefore much narrower than the shaft of the tibia 308 Regional anatomy · Leg. Like the tibia, the shaft of the bula is triangular in cross-section and has three borders and three surfaces for the attachment of muscles, intermuscular septa, and ligaments. The interosseous border of the bula faces and is attached to the interosseous border of the tibia by the interosseous membrane. The narrow medial surface faces the anterior compartment of leg, the lateral surface faces the lateral compartment of leg, and the posterior surface faces the posterior compartment of leg. The posterior surface is marked by a vertical crest (medial crest), which divides the posterior surface into two parts each attached to a different deep exor muscle. The medial surface of the lateral malleolus bears a facet for articulation with the lateral surface of talus, thereby forming the lateral part of the ankle joint. Just superior to this articular facet is a triangular area, which ts into the bular notch on the distal end of the tibia. Here the tibia and bula are joined together by the distal end of the interosseous membrane. Posteroinferior to the facet for articulation with the talus is a pit or fossa (the malleolar fossa) for the attachment of the posterior talobular ligament associated with the ankle joint. The posterior surface of the lateral malleolus is marked by a shallow groove for the tendons of the bularis longus and bularis brevis muscles. There are two apertures in the interosseous membrane, one at the top and the other at the bottom, for vessels to pass between the anterior and posterior compartments of leg. The interosseous membrane not only links the tibia and bula together, but also provides an increased surface area for muscle attachment. The distal ends of the bula and tibia are held together by the inferior aspect of the interosseous membrane, which spans the narrow space between the bular notch on the lateral surface of the distal end of the tibia and the corresponding surface on the distal end of the bula. This expanded end of the interosseous membrane is reinforced by anterior and posterior tibio bular ligaments. This rm linking together of the distal ends of the tibia and bula is essential to produce the skeletal framework for articulation with the foot at the ankle joint. Posterior compartment of leg Muscles Muscles in the posterior (exor) compartment of leg are organized into two groups, super cial and deep, separated by a layer of deep fascia. Aperture for anterior tibial ves s els Interos s eous membrane Interos s eous membrane Pos terior tibiofibular ligament B Aperture for perforating branch of fibular artery Anterior tibiofibular ligament A. As a unit, these muscles are large and powerful because they propel the body forward off the planted foot during walking and can elevate the body upward onto the toes when standing. Two of the muscles (gastrocnemius and plantaris) originate on the distal end of the femur and can also ex the knee. Deep group There are four muscles in the deep posterior compartment of leg (Table 6. Particularly active during the toe-off phase of walking when the body is propelled forward off the stance leg and the great toe is the last part of the foot to leave the ground Flexes lateral four toes Inversion and plantar exion of foot; support of medial arch of foot during walking Flexor hallucis longus Posterior surface of bula and adjacent interosseous membrane Plantar surface of distal phalanx of great toe Tibial nerve (S2, S3) Flexor digitorum longus Tibialis posterior Medial side of posterior surface of the tibia Posterior surfaces of interosseous membrane and adjacent regions of tibia and bula Plantar surfaces of bases of distal phalanges of the lateral four toes Mainly to tuberosity of navicular and adjacent region of medial cuneiform Tibial nerve (S2, S3) Tibial nerve (L4, L5) Adductor magnus mus cle posterior. The popliteus muscle acts on the knee, whereas the other three muscles act mainly on the foot. Adductor hiatus Popliteal vein Popliteal artery Arteries Popliteal artery Superior medial genicular artery Medial head of gas trocnemius mus cle Popliteus mus cle Pos terior tibial artery Superior lateral genic ular artery Sural arteries Circ umflex fibular artery Anterior tibial artery (pas s es through aperture in interos s eous membrane) the popliteal artery is the major blood supply to the leg and foot and enters the posterior compartment of leg from the popliteal fossa behind the knee. The popliteal artery passes into the posterior compartment of leg between the gastrocnemius and popliteus muscles. As it continues inferiorly it passes under the tendinous arch formed between the bular and tibial heads of the soleus muscle and enters the deep region of the posterior compartment of leg where it immediately divides into an anterior tibial artery and a posterior tibial artery. There are two large sural arteries, one on each side, that branch from the popliteal artery to supply the gastrocnemius, soleus, and plantaris muscles. In addition, the popliteal artery gives rise to branches that contribute to a collateral network of vessels around the knee joint. Fibular artery Branches tha t perforate intermus cular s eptum to enter lateral compartment Pos terior tibial artery Anterior tibial artery the anterior tibial artery passes forward through the aperture in the upper part of the interosseous membrane and enters and supplies the anterior compartment of the leg. Posterior tibial artery the posterior tibial artery supplies the posterior and lateral compartments of the leg and continues into the sole of the foot. The posterior tibial artery descends through the deep region of the posterior compartment of the leg on the super cial surfaces of the tibialis posterior and exor Perforating terminal branch of fibular artery. It passes through the tarsal tunnel behind the medial malleolus and into the sole of the foot. In the leg, the posterior tibial artery supplies adjacent muscles and bone and has two major branches, the circum ex bular artery and the bular artery: the circum ex bular artery passes laterally through the soleus muscle and around the neck of the bula to connect with the anastomotic network of vessels surrounding the knee. The bular artery parallels the course of the tibial artery, but descends along the lateral side of the posterior compartment adjacent to the medial crest on the posterior surface of the bula, which separates the attachments of the tibialis posterior and exor hallucis longus muscles. The bular artery supplies adjacent muscles and bone in the posterior compartment of the leg and also has branches that pass laterally through the intermuscular septum to supply the bularis muscles in the lateral compartment of the leg. A perforating branch that originates from the bular artery distally in the leg passes anteriorly through the inferior aperture in the interosseous membrane to anastomose with a branch of the anterior tibial artery. The bular artery passes behind the attachment between the distal ends of the tibia and bula and terminates in a network of vessels over the lateral surface of the calcaneus. Branches innervate the gastrocnemius, plantaris, and soleus muscles, and pass more deeply into the popliteus muscle. Branches to the deep muscles of the posterior compartment originate from the tibial nerve deep to the soleus muscle in the upper half of the leg and innervate the tibialis posterior, exor hallucis longus, and exor digitorum longus muscles. Sural nerve the sural nerve originates high in the leg between the two heads of the gastrocnemius muscle. It Sciatic nerve Adductor hiatus Sural nerve Veins Deep veins in the posterior compartment generally follow the arteries. Common fibular nerve Nerves Tibial nerve the nerve associated with the posterior compartment of leg is the tibial nerve. The tibial nerve passes under the tendinous arch formed between the bular and tibial heads of the soleus muscle and passes vertically through the deep region of the posterior compartment of leg on the surface of the tibialis posterior muscle with the posterior tibial vessels. The tibial nerve leaves the posterior compartment of the leg at the ankle by passing through the tarsal tunnel behind the medial malleolus. In the leg, the tibial nerve gives rise to: branches that supply all the muscles in the posterior compartment of the leg, and two cutaneous branches, the sural nerve and medial calcaneal nerve. Branches of the tibial nerve that innervate the super cial group of muscles of the posterior compartment and popliteus muscle of the deep group originate high in the leg between the two heads of the gastrocnemius muscle in Tibial nerve Sural nerve Penetrates deep fas cia Medial calcaneal nerve B A. The sural nerve supplies skin on the lower posterolateral surface of the leg and the lateral side of the foot and little toe. The medial calcaneal nerve innervates skin on the medial surface and sole of the heel. Lateral compartment of leg Muscles There are two muscles in the lateral compartment of leg- the bularis longus and bularis brevis (Table 6. Both evert the foot (turn the sole outward) and are innervated by the super cial bular nerve, which is a branch of the common bular nerve.

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