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This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Hypercalcemia is the most common life-threatening metabolic disorder associated with neoplastic diseases, occurring in an estimated 10% to 20% of all adults with cancer. It also occurs in children with cancer, but with much less frequency (approximately 0.5%–1%).[1,2,3] Solid tumors (such as lung or breast cancer tumors) as well as certain hematologic malignancies (particularly multiple myeloma) are most frequently associated with hypercalcemia.[4] Although early diagnosis followed by hydration and treatment with agents that decrease serum calcium concentrations (hypocalcemic drugs) can produce symptomatic improvements within a few days, diagnosis may be complicated because symptoms may be insidious at onset and can be confused with those of many malignant and nonmalignant diseases. However, diagnosis and timely interventions not only are lifesaving in the short term but also may enhance the patient's compliance with primary and supportive treatments and may improve quality of life.[5] When a patient has a refractory, widely disseminated malignancy for which specific therapy is no longer being pursued, the patient may want to consider withholding therapy for hypercalcemia. For patients or families who have expressed their wishes regarding end-of-life issues, this may represent a preferred timing and/or mode of death (as compared with a more prolonged death from advancing metastatic disease). This option is best considered long before the onset of severe hypercalcemia or other metabolic abnormalities that impair cognition, so that the patient may be involved in the decision making.
In this summary, unless otherwise stated, evidence and practice issues as they relate to adults are discussed. The evidence and application to practice related to children may differ significantly from information related to adults. When specific information about the care of children is available, it is summarized under its own heading.
Normal Calcium Homeostasis
Hormonal influences
Calcium homeostasis is maintained by two hormones, parathormone (parathyroid hormone or PTH) and calcitriol (1,25-dihydroxy vitamin D). Minute-to-minute regulation of serum-ionized calcium is regulated by PTH. PTH secretion is stimulated when ambient serum-ionized calcium is decreased. PTH acts on peripheral target cell receptors, increasing the efficiency of renal tubular calcium reabsorption. In addition, PTH enhances calcium resorption from mineralized bone and stimulates conversion of vitamin D to its active form, calcitriol, which subsequently increases intestinal absorption of calcium and phosphorus. Pharmacologic doses of calcitonin act as an antagonist to PTH, lowering serum calcium and phosphorus and inhibiting bone reabsorption.
Renal function
Normal, healthy kidneys are capable of filtering large amounts of calcium, which is subsequently reclaimed by tubular reabsorption. The kidneys are capable of increasing calcium excretion nearly fivefold to maintain homeostatic serum calcium concentrations. Hypercalcemia may occur, however, when the concentration of calcium present in the extracellular fluid overwhelms the kidneys' compensatory mechanisms.
Although calcium reabsorption is linked to sodium and fluid reabsorption in the proximal renal tubules, fine regulation occurs in the distal renal tubules primarily under the influence of PTH. Tumors that are capable of producing a substance similar to normal PTH such as PTH-related peptide (refer to the Mechanisms of Cancer-associated Hypercalcemia section of this summary) drive the renal tubules to increase calcium reabsorption. Under these circumstances, hypercalcemia and high calcium concentrations in urine (hypercalciuria) impair sodium and water reabsorption, causing polyuria (a calcium diuresis) with subsequent loss of circulating fluid volume (dehydration). As a consequence of dehydration, renal blood flow and the glomerular filtration rate decrease and proximal tubular calcium and sodium reabsorption increase, leading to further increases in serum calcium concentrations. Anorexia, nausea, and vomiting associated with loss of circulating fluid volume exacerbate dehydration.[6] Immobilization caused by weakness and lethargy may exacerbate calcium resorption from bone. The kidneys may be irreversibly compromised if the concentration of calcium in the glomerular filtrate exceeds its solubility, resulting in calcium precipitation in the renal tubules (nephrocalcinosis).
Bone resorption
In healthy adults before midlife, bone formation and resorption are in dynamic balance primarily through the activity of osteoblasts (bone-forming cells) and osteoclasts (bone-reabsorbing cells). Even though 99% of total body calcium is contained in bone, bone seems to have a minor function in the daily maintenance of plasma calcium levels. The normal daily exchange between bone and extracellular fluid is quite small.[7]
Mechanisms of Cancer-associated Hypercalcemia
The fundamental cause of cancer-induced hypercalcemia is increased bone resorption with calcium mobilization into the extracellular fluid and, secondarily, inadequate renal calcium clearance. Two types of cancer-induced hypercalcemia have been described: osteolytic hypercalcemia and humoral hypercalcemia. Osteolytic hypercalcemia results from direct bone destruction by primary or metastatic tumor. Humoral hypercalcemia is mediated by circulating factors secreted by malignant cells without evidence of bony disease.[8,9] It is believed that hypercalcemia results from the release of factors by malignant cells that ultimately cause calcium reabsorption from bone.[4]
One such factor is a PTH-like protein known as parathyroid hormone–related protein or peptide (PTHrP). PTHrP is a primitive protein that appears to have important roles in calcium transport and developmental biology. It shares partial amino acid sequence and conformational homology with normal PTH; binds with the same receptors on skeletal and renal target tissues; and affects calcium and phosphate homeostasis, as does PTH.[9,10,11] Increased blood levels of PTHrP have been found in patients with solid tumors but not in patients with hematologic malignancies who develop hypercalcemia.[4]
Circulating growth factors may also mediate hypercalcemia. Potential mediators include transforming growth factor-alpha and -beta, interleukin-1 and -6, and tumor necrosis factor (TNF)-alpha and -beta.[12]
Potentiating Factors
Immobility is associated with an increase in resorption of calcium from bone. Dehydration, anorexia, nausea, and vomiting that exacerbate dehydration reduce renal calcium excretion.
Hormonal therapy (estrogens, antiestrogens, androgens, and progestins) may precipitate hypercalcemia. Thiazide diuretics increase renal calcium reabsorption and may precipitate or exacerbate hypercalcemia.[13]
Hematologic malignancies may stimulate osteoclastic bone resorption through the production of cytokines such as TNF-alpha and -beta and interleukin-1 and -6, formerly referred to as osteoclast-activating factor(s).[7,9,14]
Hypercalcemia occurs more frequently in some malignancies (e.g., breast cancer, multiple myeloma, and squamous cell carcinoma of the lung) than in others. Within each disease type, the incidence of hypercalcemia varies greatly in reported series. The frequency of hypercalcemia in some of the commonly involved neoplastic disorders is shown in Table 1.
There is little correlation between the presenting symptoms of hypercalcemia and serum calcium concentrations. Rapid diagnosis of hypercalcemia may be complicated because symptoms associated with hypercalcemia are characteristically nonspecific and are easily attributed to chronic or terminal illness.[1,2] Symptom severity may be caused in part by confounding factors such as previous cancer treatment, drug disease-state interactions, or comorbid pathologies.
Few patients experience all the symptoms that have been associated with hypercalcemia (see Table 2), and some patients may not experience any symptoms. Patients with corrected total serum calcium concentrations higher than 14 mg/dL (>7.0 mEq/L or 3.49 mmol/L) are generally symptomatic.[1] It must be emphasized that clinical manifestations are closely related to the rapidity of hypercalcemia onset. Some patients develop signs and symptoms when calcium is only slightly elevated, while others with long-standing hypercalcemia may tolerate serum calcium levels higher than 13 mg/dL (>6.5 mEq/L or 3.24 mmol/L) with few symptoms. Neuromuscular manifestations are generally more marked in older patients than in young patients.
One author observed that malaise and fatigue were the most common complaints at patient presentation, followed by (in order of decreasing prevalence rate) varying degrees of obtundation, anorexia, pain, polyuria-polydipsia, constipation, nausea, and vomiting.[3]
Clinical manifestations can be categorized according to body systems and functions.
Neurologic Symptoms
Calcium ions have a major role in neurotransmission. Increased calcium levels decrease neuromuscular excitability, which leads to hypotonicity in smooth and striated muscle. Symptom severity correlates directly with the magnitude of serum-ionized calcium concentrations and inversely with their rate of change. Neuromuscular symptoms include weakness and diminished deep-tendon reflexes. Muscle strength is impaired, and respiratory muscular capacity may be decreased. Central nervous system impairment may manifest as delirium with prominent symptoms of personality change, cognitive dysfunction, disorientation, incoherent speech, and psychotic symptoms such as hallucinations and delusions. Obtundation is progressive as serum calcium concentrations increase and may progress to stupor or coma.[1,2] Local neurologic signs are not common, but hypercalcemia has been documented to increase cerebrospinal fluid protein, which may be associated with headache. Headache can be exacerbated by vomiting and dehydration.[2] Abnormal electroencephalograms are seen in patients with marked hypercalcemia.[1]
Cardiovascular Symptoms
Hypercalcemia is associated with increased myocardial contractility and irritability. Electrocardiographic changes are characterized by slowed conduction, including prolonged P-R interval, widened QRS complex, shortened Q-T interval, shortened or absent S-T segments, and possibly abrupt sloping and early peaking of the proximal limb of T waves. Hypercalcemia enhances patients' sensitivity to the pharmacologic effects of digitalis glycosides (e.g., digoxin). When serum calcium concentrations exceed 16 mg/dL (>8.0 mEq/L or 3.99 mmol/L), T waves widen, secondarily increasing the Q-T interval. As calcium concentrations increase, bradyarrhythmias and bundle branch block may develop. Incomplete or complete atrioventricular block may develop at serum concentrations around 18 mg/dL (9.0 mEq/L or 4.49 mmol/L) and may progress to complete heart block, asystole, and cardiac arrest.[1,2]
Gastrointestinal Symptoms
Gastrointestinal symptoms are probably related to the depressive action of hypercalcemia on the autonomic nervous system and resulting smooth-muscle hypotonicity. Increased gastric acid secretion often accompanies hypercalcemia and may intensify gastrointestinal manifestations. Anorexia, nausea, and vomiting are intensified by increased gastric residual volume. Constipation is aggravated by dehydration that accompanies hypercalcemia. Abdominal pain may progress to obstipation and can be confused with acute abdominal obstruction.
Renal Symptoms
Hypercalcemia causes a reversible tubular defect in the kidney, resulting in the loss of urinary concentrating ability and polyuria. Decreased fluid intake and polyuria lead to symptoms associated with dehydration, including thirst, dry mucosa, diminished or absent sweating, poor skin turgor, and concentrated urine. Decreased proximal reabsorption of sodium, magnesium, and potassium occur as a result of salt and water depletion that is caused by cellular dehydration and hypotension. Renal insufficiency may occur as a result of diminished glomerular filtration, a complication observed most often in patients with myeloma.
Although nephrolithiasis and nephrocalcinosis are usually not associated with hypercalcemia of malignancy, calcium phosphate crystals can precipitate within renal tubules to form renal calculi as a consequence of long-standing hypercalciuria. When they occur, coexisting primary hyperparathyroidism should be considered.
Bone Symptoms
Hypercalcemia of malignancy can result from osteolytic metastases or humerally mediated bone resorption with secondary fractures, skeletal deformities, and pain.
Laboratory Assessment
Normal serum calcium levels are maintained within narrow and constant limits, approximately 9.0 to 10.3 mg/dL (= 4.5–5.2 mEq/L or 2.25–2.57 mmol/L) for men and 8.9 to 10.2 mg/dL (= 4.4–5.1 mEq/L or 2.22–2.54 mmol/L) for women. Symptoms of hypocalcemia or hypercalcemia are caused by abnormalities in the ionized fraction of the plasma calcium concentration; however, ionized calcium levels are rarely checked routinely in clinical laboratories. The total plasma calcium is used to infer the ionized calcium fraction and is usually accurate, except in the setting of hypoalbuminemia. Because hypoalbuminemia is not uncommon among patients with cancer, it is necessary to correct the total plasma calcium concentration for the percent of calcium that would have been measured if the albumin level were within normal range. The calculation is as follows:
total serum calcium corrected for albumin level:[(normal albumin – patient's albumin) × 0.8] + patient's measured total calcium
This calculated value is fairly accurate, except in the presence of elevated serum paraproteins, such as in multiple myeloma. In this case, laboratory measurement of the actual ionized calcium concentration may be necessary.[1]
Calcium also binds to globulins in blood. In contrast with hypoalbuminemia, hypogammaglobulinemia has a relatively small effect on calcium protein binding. Serum total calcium concentration can be corrected for changes in globulins as follows: total serum calcium concentration varies directly by 0.16 mg/dL, 0.08 mEq/L, or 0.04 mmol/L with each 1 g/dL change in globulin concentration. In clinical practice, changes in serum globulin concentrations rarely effect clinically significant changes in the ionized calcium fraction.
Acid-base status also affects the interpretation of serum calcium values. While acidosis decreases the protein-bound fraction (consequently increasing the ionized calcium fraction), alkalosis increases protein binding. Ionized calcium fraction concentration can be corrected for changes in pH as follows: ionized calcium fraction concentration varies inversely by 0.12 mg/dL, 0.06 mEq/L, or 0.03 mmol/L with each 0.1 unit change in pH. Unlike changes in serum albumin concentration, alterations in blood pH rarely effect clinically significant changes in the ionized calcium fraction.[2]
Laboratory studies
It is important to measure the serum calcium and albumin concentrations. Other selected tests (as shown below) may be useful in some instances:
Patient Assessment
Primary assessment should include the following:[3,4]
Decision to Treat Hypercalcemia
The decision to correct clinical hypercalcemia must be considered within the context of therapeutic goals as determined by the patient, the caregivers, and the medical staff. The natural course of untreated hypercalcemia is well known to clinicians: As with hepatic or metabolic encephalopathy, untreated hypercalcemia will progress to loss of consciousness and coma. This clinical course may be desirable at the end of life in patients with intractable suffering and/or unmanageable symptoms when no further active treatment is available or desired for reversal of the primary disease process.
Individuals at risk of developing hypercalcemia may be the first to recognize symptoms such as fatigue. Patients should be advised about the ways in which hypercalcemia most frequently manifests itself and should also be given guidelines for seeking professional intervention. Preventive measures include ensuring adequate fluid intake of 3 to 4 L (100–140 fl oz per day if not contraindicated) and salt intake, nausea and vomiting control, encouraging patient mobility, attention to febrile episodes, and cautious use or elimination of drugs that may complicate management. This includes drugs that inhibit urinary calcium excretion or decrease renal blood flow, as well as medications that contain calcium, vitamin D, vitamin A, or other retinoids.[1]
Even though the gut has a role in normal calcium homeostasis, absorption is usually diminished in individuals with hypercalcemia, making dietary calcium restriction unnecessary.
Managing Hypercalcemia
Symptomatic treatment of hypercalcemia focuses first on correcting dehydration and enhancing renal calcium excretion, followed by specific hypocalcemic treatment with agents that inhibit bone resorption (e.g., calcitonin, bisphosphonates, gallium nitrate, and plicamycin).[2,3] Definitive treatment is that which effectively treats the malignant disease underlying hypercalcemia.[4] At one time, hypercalcemia was treated with aggressive intravenous hydration using isotonic saline followed by the administration of a diuretic. This volume expansion and natriuresis was performed to increase renal blood flow and enhance calcium excretion. This approach is not very effective in correcting hypercalcemia and can lead to complications of fluid overload. Intravenous fluid should be administered to correct water loss associated with calciuresis and dehydration due to vomiting. Administration of diuretics should be restricted to balancing urine output in patients who have been adequately rehydrated.[1]
The magnitude of hypercalcemia and the severity of symptoms typically form the basis for determining whether treatment is indicated. Immediate aggressive hypocalcemic treatment is warranted in patients with a corrected total serum calcium level higher than 14 mg/dL (>7 mEq/L or 3.5 mmol/L). In patients with a total corrected serum calcium concentration between 12 and 14 mg/dL (6–7 mEq/L or 3.0–3.5 mmol/L), clinical manifestations should guide the type of therapy and the urgency with which it is implemented.[2] Treatment response is indicated by resolution of symptoms attributable to hypercalcemia and by diminishing serum calcium concentrations and urinary calcium and hydroxyproline excretion.
Aggressive treatment is not generally indicated in patients with mild hypercalcemia (corrected total serum calcium level lower than 12 mg/dL [<6 mEq/L or 3.0 mmol/L]). Clear treatment decisions are problematic for patients with mild hypercalcemia and coexistent central nervous system symptoms, especially for younger patients in whom hypercalcemia is generally better tolerated. It is very important to evaluate other causes for altered central nervous system function before attributing them solely to hypercalcemia.[2]
Treatment can provide marked improvement of distressing symptoms. Polyuria, polydipsia, central nervous system symptoms, nausea, vomiting, and constipation are more likely to be managed successfully than are anorexia, malaise, and fatigue. Pain control may be improved for some patients who achieve normocalcemia.[5][Level of evidence: III] Effective calcium-lowering therapy usually improves symptoms, enhances the quality of life, and may allow patients to be managed in a subacute, ambulatory, or home care setting.
After normocalcemia is achieved, serum calcium should be monitored serially, with the frequency determined by anticipated duration of response to any particular hypocalcemic regimen.
Mild Hypercalcemia
Mild hypercalcemia is defined as corrected total serum calcium level lower than 12 mg/dL (<6 mEq/L or 3.0 mmol/L).
Hydration followed by observation is a treatment option. This option should be considered for asymptomatic patients who are about to be treated for tumors that are likely to respond to antineoplastic treatment (e.g., lymphoma, breast cancer, ovarian cancer, head and neck carcinoma, and multiple myeloma).[6]
In symptomatic patients or when tumor response to therapy is expected to occur slowly, therapy for hypercalcemia should be implemented to manage symptoms and stabilize patients' metabolic states. Additional ancillary interventions should be directed toward controlling nausea and vomiting, encouraging mobility, noting febrile episodes, and the minimal use of sedating medications.[6]
Moderate to Severe Hypercalcemia
Moderate to severe hypercalcemia is defined as corrected total serum calcium equal to 12 to 14 mg/dL (6–7 mEq/L or 3.0–3.5 mmol/L).
Rehydration is the essential first step in treating moderate or severe hypercalcemia. Although fewer than 30% of patients achieve normocalcemia with hydration alone, replenishing extracellular fluid, restoring intravascular volume, and saline diuresis are fundamental to initial therapy. Adequate rehydration may require 3,000 to 6,000 mL of 0.9% sodium chloride for injection (normal saline) within the first 24 hours to restore fluid volume. Restoring normal extracellular fluid volume will increase daily urinary calcium excretion by 100 to 300 mg. Clinical improvement in mental status and nausea and vomiting is usually apparent within 24 hours for most patients; however, rehydration is a temporizing intervention. If definitive cytoreductive therapies (surgery, radiation, or chemotherapy) are not forthcoming, hypocalcemic agents must be used to achieve long-term control.
Thiazide diuretics increase renal tubular calcium absorption and may exacerbate hypercalcemia. Thus, thiazide diuretics are contraindicated in hypercalcemia patients. Loop diuretics (e.g., furosemide, bumetanide, and ethacrynic acid) induce hypercalciuria by inhibiting calcium reabsorption in the ascending limb of the loop of Henle, but they should not be administered until fluid volume is restored. Otherwise, loop diuretics can exacerbate fluid loss, further reducing calcium clearance. Because sodium and calcium clearance are closely linked during osmotic diuresis, loop diuretics will depress the proximal tubular resorptive mechanisms for calcium, increasing calcium excretion to 400 to 800 mg per day.
Moderate doses of furosemide (20–40 mg every 12 hours) increase saline-induced urinary calcium excretion and are useful in preventing or managing fluid overload in adequately rehydrated patients. Aggressive treatment with furosemide (80–100 mg every 2–4 hours) is problematic because it requires concurrent administration of large volumes of saline to prevent intravascular dehydration.[7][Level of evidence: III] This, in turn, requires intensive hemodynamic monitoring (to avoid volume overload and cardiac decompensation) and frequent serial measurements of urinary volume and electrolytes (to prevent life-threatening hypophosphatemia, hypokalemia, and hypomagnesemia).[6,8][Level of evidence: IV]
Pharmacologic Inhibition of Osteoclastic Bone Resorption
Described below are therapies that can inhibit osteoclastic bone resorption. The most widely used modality for this purpose is a bisphosphonate (such as pamidronate). The use of other agents such as calcitonin, mithramycin, or gallium nitrate is less common.
Bisphosphonates are one of the most effective pharmacologic alternatives for controlling hypercalcemia. They bind to hydroxyapatite in calcified bone, rendering it resistant to hydrolytic dissolution by phosphatases, thereby inhibiting both normal and abnormal bone resorption.[9] Bisphosphonate treatment reduces the number of osteoclasts in sites undergoing active bone resorption and may prevent osteoclast expansion by inhibiting differentiation from their monocyte-macrophage precursors.[10][Level of evidence: IV] Bisphosphonates have variable effects on other aspects of bone remodeling, such as new bone formation and mineralization. For example, etidronate at clinically relevant dosages (300–1,600 mg/day) inhibits new bone formation and mineralization.[11][Level of evidence: II] With prolonged etidronate use, osteomalacia and pathologic fractures may occur.[12][Level of evidence: III] In contrast, clodronate, pamidronate, and alendronate are 10, 100, and 1,000 times more potent inhibitors of bone resorption than etidronate and are clinically useful at dosages that are less likely to adversely affect new bone formation and mineralization.[13][Level of evidence: IV];[14,15,16][Level of evidence: II] Many bisphosphonates may be useful in treating hypercalcemia of malignancy. In the United States, etidronate and pamidronate are the only bisphosphonates approved for treating hypercalcemia.
In a randomized double-blind study comparing pamidronate with etidronate for the treatment of cancer-related hypercalcemia, pamidronate (60 mg intravenous [IV] single dose over 24 hours) has been demonstrated to be more effective with respect to serum calcium reduction and duration of hypocalcemic response than etidronate (7.5 mg/kg of body weight per day administered over 2 hours as a daily IV infusion for 3 consecutive days).[17][Level of evidence: I] This finding has led to the diminished use of etidronate.[1]
In treating moderate hypercalcemia (corrected serum calcium <13.5 mg/dL, <6.75 mEq/L, or <3.37 mmol/L), pamidronate 60 to 90 mg IV is administered over 2 to 24 hours.[18] Onset of pamidronate's effect is apparent within 3 to 4 days, with maximal effect within 7 to 10 days after commencing treatment. The effect may persist for 7 to 30 days.[19][Level of evidence: I] It is recommended that a minimum of 7 days elapse before re-treatment with pamidronate to assess full response to the initial dose.[18] Adverse effects include transient low-grade temperature elevations (1°C–2°C) that typically occur within 24 to 36 hours after administration and persist for up to 2 days in up to 20% of patients. Pamidronate has also been used successfully in children, with similar side effects.[20][Level of evidence: III] Other bisphosphonates (except clodronate) may also produce transient temperature elevations; the incidence of temperature elevation, nausea, anorexia, dyspepsia, and vomiting may be increased by rapid administration.[21][Level of evidence: I];[22][Level of evidence: III] New-onset hypophosphatemia and hypomagnesemia may occur; pre-existing abnormalities in the same electrolytes may be exacerbated by treatment. Serum calcium may fall below the normal range, and hypocalcemia (typically asymptomatic) may result. Renal failure has only been reported after rapid etidronate and clodronate injection, but rapid administration should be avoided with all bisphosphonates.[23][Level of evidence: III] Intravenous pamidronate administration has been associated with acute-phase responses, including transiently decreased peripheral lymphocyte counts. Local reactions (thrombophlebitis, erythema, and pain) at the infusion site have been reported.[21]
The use of subcutaneous (SC) administration of clodronate has been explored. Initial experience suggested that clodronate was well tolerated subcutaneously; however, aminobisphosphonates such as pamidronate resulted in local irritation.[24] In a subsequent study, 37 inpatients with terminal cancer received 45 clodronate infusions.[25][Level of evidence: II] Clodronate, 1,500 mg in 1 L of normal saline, was administered via a 23-gauge, ¾-inch butterfly needle into the SC space. All the infusions were completed, and none required discontinuation due to discomfort. The authors concluded that their results suggested that SC clodronate is an effective treatment for hypercalcemia of malignancy and is associated with minimal toxicity. This technique has advantages in the care of terminally ill patients at home and may avoid the need for hospital admission and/or IV administration. In addition, SC administration in the hospital setting has advantages for patients for whom an IV site may be problematic.
Calcitonin and plicamycin have a more rapid hypocalcemic effect than bisphosphonates; however, pamidronate has several advantages over nonbisphosphonate therapies. In comparison with plicamycin, response rates are greater among patients treated with pamidronate.[26][Level of evidence: I] Pamidronate more frequently reduces serum calcium concentrations to normocalcemic ranges than either calcitonin or plicamycin.[26,27][Level of evidence: I] In addition, pamidronate's hypocalcemic effect is dose related and sustained after repeated administration, and it generally persists longer than the effects produced by either calcitonin or plicamycin therapies.[19][Level of evidence: I] Pamidronate lacks the renal, hepatic, and platelet toxic effects associated with plicamycin.
Calcitonin is a peptide hormone secreted by specialized cells in the thyroid and parathyroid. Its synthesis and secretion normally increase in response to high concentrations of serum-ionized calcium. Calcitonin opposes physiologic effects of parathyroid hormone on bone and renal tubular calcium resorption; however, it is not known whether calcitonin has a significant role in calcium homeostasis. Nevertheless, calcitonin rapidly inhibits calcium and phosphorous resorption from bone and decreases renal calcium reabsorption. Calcitonin derived from salmon is much more potent and is longer acting than the human hormone. The initial dose schedule is 4 IU/kg of body weight per SC dose or intramuscular (IM) dose every 12 hours. Dose and schedule may be escalated after 1 or 2 days to 8 IU/kg every 12 hours, and finally to 8 IU/kg every 6 hours if the response to lower doses is unsatisfactory. Unfortunately, tachyphylaxis commonly occurs. With repeated use, calcitonin's beneficial hypocalcemic effect wanes, even at the upper recommended limits of dose and schedule, so that its calcium-lowering effect lasts for only a few days. In patients who are responsive to calcitonin, its combination with bisphosphonates may hasten the onset and duration of a hypocalcemic response caused by calcitonin's rapid (within 2–4 hours) onset of action.[28][Level of evidence: II];[29][Level of evidence: IV]
Calcitonin is usually well tolerated; adverse effects include mild nausea, transient cramping abdominal pain, and cutaneous flushing. Calcitonin is most useful within the first 24 to 36 hours of treatment of severe hypercalcemia and should be used in conjunction with more potent but slower-acting agents.
Plicamycin (also referred to as mithramycin) is an inhibitor of osteoclast RNA synthesis. It has been shown to inhibit bone resorption in vitro and is clinically effective in the presence or absence of bone metastases. Onset of response occurs within 12 hours of a single IV dose of 25 to 30 μg/kg of body weight given as a short infusion for 30 minutes or longer. Maximum response, however, does not occur until approximately 48 hours after administration and may persist for 3 to 7 days or more after administration. Repeated doses may be given to maintain plicamycin's hypocalcemic effect but should not be given more frequently than every 48 hours to determine the maximum calcium-lowering effect produced by previous doses.[30] Multiple doses may control hypercalcemia for several weeks, but rebound hypercalcemia usually occurs without definitive treatment against the underlying malignancy.[31] Although single-dose treatment of hypercalcemia is generally well tolerated with few adverse effects,[32][Level of evidence: II] dysfibrinogenemia [33][Level of evidence: III] and nephrotoxicity [34] have been reported after single doses (20–25 μg/kg). Rapid IV administration is associated with nausea and vomiting.[31] High and repeated doses predispose the patient to thrombocytopenia, a qualitative platelet dysfunction that may be associated with a bleeding diathesis, transient increases in hepatic transaminases, nephrotoxicity (decreased creatinine clearance, increased serum creatinine and blood urea nitrogen, potassium wasting, and proteinuria), hypophosphatemia, a flulike syndrome, dermatologic reactions, and stomatitis.[31,34];[35][Level of evidence: II];[36,37,38,39][Level of evidence: III]
Gallium nitrate
Gallium nitrate was developed as an antineoplastic agent that was coincidentally found to produce a hypocalcemic effect. Gallium nitrate interferes with an adenosine triphosphatase–dependent proton pump in the membrane of osteoclasts. This impairs osteoclast acidification and the dissolution of the underlying bone matrix.[1] Gallium nitrate has been shown to be superior to etidronate in the percentage of patients who achieve normocalcemia and in the duration of normocalcemia.[40][Level of evidence: I] Drawbacks to its use include a continuous 5-day IV infusion schedule (200 mg/m2 of body surface area per day) [6] and the potential for nephrotoxicity, particularly when it is used concurrently with other potentially nephrotoxic drugs (e.g., aminoglycosides and amphotericin B).[1]
Gallium nitrate has also been given by daily SC injection to prevent bone resorption and maintain bone mass in patients with multiple myeloma.[41][Level of evidence: I]
Other Therapeutics for Hypercalcemia
Glucocorticoids have efficacy as hypocalcemic agents primarily in steroid-responsive tumors (e.g., lymphomas and myeloma) and in patients whose hypercalcemia is associated with increased vitamin D synthesis or intake (sarcoidosis and hypervitaminosis D).[42][Level of evidence: III];[43][Level of evidence: II] Glucocorticoids increase urinary calcium excretion and inhibit vitamin D–mediated gastrointestinal calcium absorption. Response, however, is typically slow; 1 to 2 weeks may elapse before serum calcium concentrations decrease. Oral hydrocortisone (100–300 mg) or its glucocorticoid equivalent may be given daily; however, complications of long-term steroid use limit its usefulness even in responsive patients.
Phosphate offers a minimally effective chronic oral treatment for mild to moderate hypercalcemia. It is most useful after successful initial reduction of serum calcium with other agents and should probably be reserved for patients who are both hypercalcemic and hypophosphatemic. The usual treatment is 250 to 375 mg per dose given 4 times daily (1–1.5 g of elemental phosphorus per day) to minimize the potential for developing hyperphosphatemia.[44] Supranormal phosphate administration results in decreased renal calcium clearance and presumably decreases serum calcium concentrations by precipitating calcium into bone and soft tissues.[45,46][Level of evidence: II] Extraskeletal precipitation of calcium in vital organs may have adverse consequences and is especially significant after intravenous administration.[6];[47,48][Level of evidence: III] IV administration of phosphate produces a rapid decline in serum calcium concentrations but is rarely used because there are safer and more effective antiresorptive agents for life-threatening hypercalcemia (calcitonin and plicamycin). Hypotension, oliguria, left ventricular failure, and sudden death can occur as a result of rapid IV administration. Contraindications for phosphate include normophosphatemia, hyperphosphatemia, and renal insufficiency. Oral phosphate should be given at the lowest dose possible to maintain serum phosphorous concentrations lower than 4 mg/dL 1 to 2 hours after administration.
The use of phosphates is limited by individual patient tolerance and toxicity; 25% to 50% of patients cannot tolerate oral phosphates.[8] Oral phosphate–induced diarrhea may be initially advantageous in patients who have experienced constipation secondary to hypercalcemia; it is the predominant and dose-limiting adverse effect for oral therapy and frequently prevents dosage escalation of more than 2 g of neutral phosphate per day.[6]
Dialysis is an option for hypercalcemia that is complicated by renal failure. Peritoneal dialysis with calcium-free dialysate fluid can remove 200 to 2,000 mg of calcium in 24 to 48 hours and decrease the serum calcium concentration by 3 to 12 mg/dL (1.5–6 mEq/L or 0.7–3 mmol/L). Ultrafiltrable calcium clearance may exceed that of urea with calcium-free dialysate exchanges of 2 L each every 30 minutes.[49] Hemodialysis is equally effective.[50][Level of evidence: III];[51][Level of evidence: IV] Because large quantities of phosphate are lost during dialysis and phosphate loss aggravates hypercalcemia, serum inorganic phosphate should be measured after each dialysis session, and phosphate should be added to the dialysate during the next fluid exchange or to the patient's diet.[52][Level of evidence: III] It is recommended, however, that phosphate replacement should be limited to restoring serum inorganic phosphate concentrations to normal rather than supranormal.[44]
Prostaglandin synthesis inhibitors
Prostaglandin synthesis inhibitors such as the nonsteroidal anti-inflammatory drugs may have some efficacy in the management of cancer-induced hypercalcemia. The E-series prostaglandins mediate bone resorption. Despite experimental evidence, however, aspirin and other nonsteroidal drugs have demonstrated only modest clinical response rates in controlling hypercalcemia. For patients who are unresponsive to or unable to tolerate other agents, aspirin may be given to produce a serum salicylate concentration equal to 20 to 30 mg/dL, or 25 mg indomethacin may be given orally every 6 hours.[53,54,55][Level of evidence: II];[56][Level of evidence: III]
Serum calcium was normalized for a median of 34 days (range, 4–115) in 9 of 13 patients with various solid tumors given IV cisplatin at 100 mg/m2 of body surface area over 24 hours. Patients were re-treated as frequently as every 7 days if necessary to maintain serum calcium concentrations lower than 11.5 mg/dL (<5.75 mEq/L or 2.87 mmol/L). Four of seven patients responded to repeated treatment. Responders achieved a statistically significant difference in serum calcium levels from baseline on the tenth day after treatment, which continued thereafter. Serial tumor measurements revealed that the hypocalcemic response did not correlate with tumor shrinkage; there was no detectable antitumor response in any measurable or evaluable disease.[57]
Future pharmacologic management is likely to combine osteoclastic inhibitors with cytotoxic or endocrine therapy.[9]
Patient and Family Education
Hypercalcemia compromises the patient's quality of life and can be life-threatening if not promptly recognized and treated. Individuals at risk and their caregivers should be made aware that hypercalcemia is a possible complication. Patients and their significant others should be advised about the types of symptoms that may occur with hypercalcemia, preventive measures, exacerbating factors, and when to seek medical assistance.[58] They should be taught measures to diminish the symptoms of hypercalcemia such as maintaining mobility and ensuring adequate hydration.
Supportive Care
Despite encouraging developments in pharmacologic management, the prognostic implications related to hypercalcemia remain relatively grim. Only patients for whom effective anticancer therapy is possible can be expected to experience a longer survival.
The adverse effects of therapy need to be prevented or recognized and managed. Fluid overload and electrolyte imbalance can occur during initial therapy. Serum sodium, potassium, calcium, phosphate, and magnesium concentrations may be markedly decreased. Electrolyte levels should be monitored at least daily, and clinical signs and symptoms should be assessed at least every 4 hours when hydration or specific hypocalcemic drug treatments are being implemented.
The management of symptoms of hypercalcemia is crucial. Preventing accidental or self-inflicted injury as a consequence of the patient's altered mental status is a priority during acute management. Until serum calcium decreases, additional pharmacologic interventions may be necessary to control nausea, vomiting, and constipation.
Any acute severe exacerbation or development of new bone pain should be evaluated for the presence of a pathological fracture. Many health care facilities institute fracture precautions for patients with metastatic disease to the bone. These precautions include gentle handling when moving or transferring patients and fall-prevention strategies. Maximum mobility and weight-bearing exercises are desirable.
Supportive care in terminal stages typically consists of comfort measures for patients and their caregivers. Changes in mentation and behavior may be especially distressing to family members.
Psychosocial Management
Supportive management of delirium, agitation, or changes in mental status is implemented in patients with hypercalcemia. Primary treatment of hypercalcemia and/or its underlying etiology eventually leads to the resolution of changes in mental status in most of these patients. Some patients present with clinically significant and distressing changes in mental status, agitation, or delirium that warrants management or control. (Refer to the PDQ summary on Delirium for more information.) Clinical experience supports the use of neuroleptic medications such as haloperidol (0.5–5.0 mg IV or by mouth 2–4 times a day) alone or in combination with benzodiazepines (e.g., 0.5–2.0 mg of lorazepam IV or by mouth 2–4 times a day) for the control of agitation and confusion. This enhances patient and family comfort and allows for easier institution of primary therapies. The use of benzodiazepines in these situations should be reserved for instances in which sedation (and not improvement in mental status) is the primary goal of the intervention.
The relationship between mental status and serum calcium levels is variable. Some patients will not manifest improvement in mental status until days to a week or more after serum calcium levels are in the normal range; others will display improvement before laboratory values catch up.
Many times, lethargy is a presenting symptom of hypercalcemia. Lethargic patients are often mistakenly believed by family (and sometimes by staff) to be depressed before the actual etiology of the mental-status changes becomes known. The differential diagnosis is generally straightforward in that many of these patients will lack the cognitive or ideational symptoms of a mood disorder (hopelessness, helplessness, anhedonia, guilt, worthlessness, or thoughts of suicide) and instead will appear mainly lethargic and apathetic; formal testing of mental status is likely to reveal cognitive deficits. This is an important distinction to be made, as the introduction of antidepressant drugs during an organic confusional episode can worsen confusion.
Management of hypercalcemia
Hypercalcemia generally develops as a late complication of malignancy; its appearance has grave prognostic significance. It remains unclear, however, whether death is associated with hypercalcemic crisis (uncontrolled or recurrent progressive hypercalcemia) or with advanced disease. Currently available hypocalcemic agents have little effect in decreasing the mortality rate among patients with hypercalcemia of malignancy. Although there is some disagreement among investigators who have evaluated survival among patients with cancer-related hypercalcemia,[59,60,61,62] it has been observed that 50% of patients with hypercalcemia die within 1 month and 75% within 3 months after starting hypocalcemic treatment. In the same study, patients with hypercalcemia who responded to specific antineoplastic treatment were found to have a slightly greater survival advantage over nonresponders. Other prognostic variables shown to correlate with longer survival included serum albumin concentration (direct correlation), serum calcium concentrations after treatment (inverse correlation), and age (inverse correlation).[5] In contrast with their modest effect on survival, marked but differential response rates were observed after hypocalcemic treatments as a factor of symptom type. The most substantial improvements occurred in renal- and central nervous system–related symptoms (nausea, vomiting, and constipation). Symptoms of anorexia, malaise, and fatigue improved, but less completely.[5]
Check NCI's list of cancer clinical trials for U.S. supportive and palliative care trials about hypercalcemia of malignancy that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Editorial changes were made to this summary.
This summary is written and maintained by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
If you have questions or comments about this summary, please send them to Cancer.gov through the Web site's Contact Form. We can respond only to email messages written in English.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the pathophysiology and treatment of hypercalcemia. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
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Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Supportive and Palliative Care Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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The preferred citation for this PDQ summary is:
National Cancer Institute: PDQ® Hypercalcemia. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/supportivecare/hypercalcemia/HealthProfessional. Accessed <MM/DD/YYYY>.
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Among of the biggest news of the Adobe AIR 3 release is the Native Extensions feature. If you want to get started with this, or maybe just try it, you should check out the Native Extensions page on Adobe Developer Connection.
There are five examples so far:
- Gyroscope (iOS/Android)
- NetworkInfo (iOS) – retrieves information about the network interfaces on an iOS device
- Vibration (iOS/Android) – make the device vibrate
- iBattery (iOS) – gets the battery status (unknown, unplugged, charging, or full) of an iOS device
- .NET Image Encoder (Windows) – encodes a bitmap into BMP, JPEG, or PNG format using Microsoft .NET Framework 4
The first three extensions were created by Adobe engineers, the last two by community. As I said before I'm looking forward to seeing many more extensions created and having a central place to go for all of them.

subset: commoncrawl


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Cardinals take down Reds 5-3 in home opener
ST. LOUIS — Home opener hoopla was no distraction at all for Michael Wacha. Neither was the 49-degree chill for the first pitch.
The 22-year-old rookie was definitely excited about the occasion and the opportunity. Just like last fall when he was the breakout pitching star of the postseason, he fed off the atmosphere.
"Huge crowd out there, a lot of energy," Wacha said after the St. Louis Cardinals beat the Cincinnati Reds 5-3 on Monday. "It's a lot of fun pitching in front of your home crowd, 40,000-plus fans.
"I don't know who wouldn't thrive off those kind of situations."
Wacha outdid Tony Cingrani in a rematch of young power arms, and the Cardinals got a three-run double from Yadier Molina in the first inning.
"I didn't have my fastball, so what are you going to do? I just tried to battle," Cingrani said. "One bad pitch and it cleared the bases."
A standing-room crowd of 47,492, the largest at 9-year-old Busch Stadium, braved daylong rain to greet the National League champions and take a look at the new Ballpark Village. Hundreds milled about the attached complex, which features five sports bars and rooftop seating.
The Cardinals bunched three hits and a walk over the first five hitters to take the early lead against Cingrani (0-1), who allowed two hits in seven scoreless innings against the Cardinals six days earlier in Cincinnati.
The Cards went 1 for 18 before adding RBIs from Matt Holliday and Allen Craig off Trevor Bell in a two-run seventh.
St. Louis ended a three-game losing streak on opening day, including a blowout loss to the Reds last year.
Wacha (1-0) hadn't allowed a run in 21 career innings against the Reds before back-to-back doubles by Brayan Pena and pinch-hitter Roger Bernadina in the fifth cut the Cardinals' lead to 3-1.
The NL championship series MVP benefited from two double-play balls in six stingy innings and has permitted one run in 13 2-3 innings his first two starts.
Wacha threw 82 pitches before getting lifted for a pinch hitter with the Cardinals up by two runs and two on in the sixth. St. Louis manager Mike Matheny wanted to take a shot at putting the Reds away, but thought the right-hander had plenty left.
"That was more of a situation of what's best for the day, what's best for that particular game," Matheny said.
Cingrani needed 31 pitches to get through the first and lasted four innings, striking out five but walking four. Matheny said before the game that his hitters had been a "click off" with timing against the 24-year-old lefty last week and should benefit from another chance so soon.
Pena said he wasn't trying to make excuses but thought Cingrani was bothered by the elements.
"The baseball was slippery. He couldn't grab his breaking ball the way he wanted," Pena said.
Peter Bourjos moved up to second in the order and got his first two hits of the season after an 0-for-13 start. Craig got his third hit and third RBI of the season after entering 2 for 22.
Seeing Wacha once again didn't do the Reds any good. They've totaled 18 runs in seven games.
"Right now, almost collectively, we've struggled to do anything with guys in scoring position," Cincinnati manager Bryan Price said. "But that'll change. It's tough to sit through it."
The start of the game was delayed 12 minutes after the inclement weather combined with pregame ceremonies that featured the traditional grand entrance with players, coaches and Hall of Famers touring Busch Stadium on the back of convertibles and trucks. A team of Clydesdales was kept in the stable due to concerns the field might be damaged.
Billy Hamilton doubled to start the game and the Reds put the leadoff man on base in the first four innings but were undone by two double plays.
Zack Cozart broke an 0-for-22 slump to start the season with a bloop RBI single, and pinch-hitter Neftali Soto had a sacrifice fly for his first career RBI in the ninth against St. Louis closer Trevor Rosenthal, who gave up his first runs at home since Aug. 15 against Pittsburgh.
The Cardinals opened the first with singles by Matt Carpenter and Bourjos, and Holliday walked to load the bases with none out. Craig struck out before Molina cleared the bases with a drive to left-center on a 1-2 pitch.
NOTES: Lance Lynn (1-0, 5.40 ERA) opposes Homer Bailey (0-1, 8.31) in the second game of the series, another rematch from the season-opening series in Cincinnati. Lynn allowed three runs in five innings and Bailey gave up four runs in 4 1/3 innings in St. Louis' 7-6 win. … The Reds anticipate activating reliever Jonathan Broxton (forearm) from the 15-day disabled list Tuesday. The team held off making the move Monday to give Broxton two days off after pitching on consecutive days.


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Watch It: Wild at Heart
Wild at Heart features brutal, with-my-bare-hands-type murder; a very possessive mother who deals with stress by covering her entire face and neck with red lipstick; a mysterious crime boss named Mr. Reindeer; lots of close-ups of fire; hot, loud sex; and Willem DeFoe's creepiest role ever—which is saying something.
But deep down, it's just an old-fashioned love story. [ Continue Reading ]


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Faster closed-loop control for compressors has helped Alberta EnviroFuels, a division of Keyera Corp. of Calgary, Alberta, Canada, better produce iso-octane, a blending component of automotive gasoline, from a feedstock of field butane. Several of the internal process steps require high-purity hydrogen. This hydrogen stream is acquired by compressing a low-pressure gas stream that contains about 50% hydrogen by weight, and then feeding the compressed stream into a hydrogen recovery unit. Figure 1 shows one of Alberta EnviroFuel's four hydrogen compressors.
Because the feed stream into the hydrogen recovery unit is very light, process designers selected positive displacement compressors, specifically wet screw compressors, to accomplish the feed compression. Since the demand for high-purity hydrogen can vary from moment to moment, the compression process also needs to provide a method for matching the volume of feed gas delivered by the screw compressors to the demand for purified hydrogen. Instead of supplying a traditional external spillback control valve (which would have been manipulated based on holding a constant discharge pressure), the compressor vendor suggested use of screw compressors with internal slide valves. Extending or retracting these internal slide valves varies the displaced volume (the effective compressor capacity).
Smooth precision
"The challenge that we faced," said Phil Prins, senior process control engineer of Alberta EnviroFuels, "is that while we are always striving for precise control of our process variables—the capacity of the compressors in this case—we often put an even higher premium on smooth control." And positioning of the internal slide valves with the original control scheme was neither precise nor smooth.
Technically, Alberta EnviroFuels' screw compressors are two-stage models. The first stage takes the gas to 250 psi and the second stage goes from 250 psi to 500 psi. Each stage has its own slide valve. The motors driving the compressors produce about 1250 hp. The compressor is 8 ft long by 2.5 ft across. Hydraulic actuators control the slide valve since moderately high-pressure oil was already available to seal the rotor gap inside the compressor and lubricate the radial and thrust bearings.
The company initially controlled the slide valves via a distributed control system (DCS) that communicated a position target for each slide valve, using a 4-20 mA analog link to a Modicon programmable logic controller (PLC). In turn, the PLC energized solenoids to activate two-position hydraulic shuttle valves to energize cylinders to move each compressor slide valve in one direction or the other, based on whether the pressure was above or below its setpoint.
"We had a very hard time getting the slide valves to move smoothly and precisely to the target position, and so we couldn't hold pressures at equilibrium," said Prins. "In the field we had all sorts of restrictors and check valves attempting to try to convert essentially on/off controls into proportional controls. In the PLC, we had all sorts of timers and deadbands trying to balance process needs with hardware limitations." The application needed controls to actuate the slide valves with "very precise and smooth movements," continued Prins. "Dealing with the hydraulics is an area where we don't have a lot of experience."
Proportional servo valves
After studying the problem and consulting with engineers from motion control distributor PQ Systems of Burnaby, British Columbia, Canada, it was decided to replace much of the field hardware, and to use direct-drive proportional servo valves so that tighter control of the hydraulics could be accomplished (Figure 2). That raised the question of what would replace the position control software, previously in the PLC. Several PLC- and DCS-based options were considered, but the PQ Systems engineer advised that an easier and more effective way would be to interface the DCS setpoint signal for each slide valve to an electro-hydraulic motion controller, designed for smooth and precise closed-loop control of hydraulic actuators in all environmental conditions.
Oil temperature was one of the variables that caused the original valve control system to behave poorly. During normal compressor operation the oil temperature is fairly consistent. However, when a compressor is in standby mode (not running, but available for immediate start-up), the oil temperature can vary significantly. This can have an effect on the time that the valve takes to move. The old system with the PLC controlling the bidirectional shuttle valves didn't handle the temperature differences smoothly.
PQ systems recommended a motion controller (Figure 3) that can simultaneously control two motion axes, so one controller can control both slide valves in the application. For feedback on the position of the slide valves, the controller was connected to a potentiometer mounted on each slide, producing an analog voltage relating to slide extension that can be read directly by the controller. Figure 4 shows how the system components are connected.
2-axis control
Another analog input module on the controller connects to the output of the DCS-based process pressure controllers. Since the same DCS control scheme is used in the upgraded system, functioning in the same manner, the compressor's operator interface needed only very minor changes as a result of the upgrade. This was a big plus for plant operators. The controller improved the way the controls work: The old hardware led to control loops that tended to be undertuned, which meant that the controls didn't respond well to upset conditions, and operators had to get involved if quick action was needed.
Now with the closed-loop controller running at 1000 loops per second, tuning can be optimized and the controls respond more quickly and automatically to changing conditions. As a result, the hydrogen purification process maintains the target pressure more precisely and responds to environmental changes more quickly. Also, the control system no longer induces its own fluctuations that plagued the previous controls.
PQ Systems applications specialist Rob Nash did the initial controller programming, with the assistance of Delta Computer engineer Don Denman. Those involved said the controller is easy to program, and since the design was initially implemented, Alberta EnviroFuels engineer Prins has made changes to tweak the system's operation. The controller uses an Ethernet interface, so Prins created an interface with the controller and made software upgrades from his office desk over the corporate network. "That's a lot more convenient than making trips to the plant floor and back," said Prins.
Tuning wizard
The tuning wizard and the plotting functions supported by the software provided "were very helpful features used during commissioning," said Nash. "The entire commissioning process for both slide valves took only a couple of hours," he continued. "Without plotting it would have taken much longer, and logistically, since the controller was located across the plant outside of the hazardous area of the compressor and therefore out of sight visually, tuning of a slide valve without plotting capability would have been nearly impossible." Figure 5 shows a typical plot produced by software.
This application provides an example of how a programmable electro-hydraulic motion controller can be used to bring a process under control that was previously impacting the productivity of a manufacturing operation.
"Comparing the standard deviations of the discharge pressure distribution before and after the controls upgrade, we saw an improvement of about 70%," said Prins. As Alberta EnviroFuels found out, where precise motion and tight tolerances are involved, it pays to select a control system that is designed for the task. In this case, a motion controller had a clear advantage over a PLC.
- Don Denman is senior applications engineer, Delta Computer Systems Inc. Edited by Mark T. Hoske, content manager, CFE Media, Control Engineering and Plant Engineering, firstname.lastname@example.com.
See other motion control articles at the bottom.
Key concepts
- Controllers and actuators need to work together smoothly and precisely in many applications.
- Work-around solutions included restrictors and check valves.
- Updates included proportional servo valves and an electro-hydraulic motion controller.
Consider this
Can a new controller offer higher quality through more precise closed-loop control?
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Blood Pressure Monitors is the force that circulates blood throughout the body. Normal blood pressure is vital for life. Without that pressure that forces our blood to flow around the body, no oxygen or nutrients would be delivered through our body for its survival.
In this fast-paced world, people are often exposed to an undesirable amount of stress as well as health problems, which leads to an irregularity of blood pressure. It should be monitored on a daily basis. So, to avoid the hassle of going to the doctor, we provide you with a range of Blood Pressure Devices, all at the comfort of your homes.
Cardiovascular diseases are one of the leading cause of deaths around the world. A sphygmomanometer is also known as a BP monitor, is a device used to measure blood pressure digitally. There is a range of Brands for Blood Pressure Device available on our website that provides accurate and instant blood pressure results. Automatic BP monitors from AccuSure by Dr. Gene helps keep track of your health.
We have a range of Omron BP Monitors, which comes with a smartphone application that connects to Omron Bluetooth Smart devices and provides access to device measurements, history graphs and averages. Other brands like Karma, Perfecxa, Rossmax, etc. are also available.
All these Blood Pressure Monitors helps you to be aware of your health on a regular basis. TabletShablet offer a great deal of discount on these devices.


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WASHINGTON — The chairman of the Joint Chiefs of Staff said Friday the U.S. hasn't raised its military readiness or alert status because of the instability in Egypt, even though the Obama administration is very concerned about the instability there.
Animated Boehner: 'There's nothing complex about the Keystone Pipeline!'
House Speaker John Boehner became animated Tuesday over the proposed Keystone Pipeline, castigating the Obama administration for not having approved the project yet.
- Budget deficits shrinking but set to grow after 2015
- Senate readies another volley on unemployment aid
- Obama faces Syria standstill
- Fluke files to run in California
- Christie acknowledges federal subpoena
- Obama says Fox News's O'Reilly 'absolutely' unfair in extended interview
- Christie security officer hit with shoplifting charges
- Animated Boehner: 'There's nothing complex about the Keystone Pipeline!'
More politics
Adm. Mike Mullen also said there shouldn't be any rush to terminate military assistance to President Hosni Mubarak's government.Story: Senate backs measure seeking change in Egypt
Mullen also reinforced President Barack Obama's call for a "peaceful, nonviolent transition" and said that decision ultimately must be made by the Egyptian people and their government.
U.S. assistance to Egypt
As for U.S. assistance to Egypt, which has averaged about $1.3 billion a year, Mullen said Congress shouldn't move too hastily to cancel the program. Mullen says on ABC's "Good Morning America" he would "caution against doing anything until we know what's really going on."
Mullen said he has been in regular communication with his Egyptian counterpart and he doesn't believe the army will attack the demonstrators. He said military personnel in Egypt have sought to remain neutral and "they really want to continue to do that."
The Navy admiral said the United States is in a higher state of "awareness" but not in a higher state of alert.
Copyright 2011 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.


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Anyone in northeast Colorado interested in becoming a basketball official for junior high and high school games will soon have the opportunity.
Classes for new officials will be held at Akron High School, beginning in September. The classes will be held at 7 p.m. every Monday from Sept. 8 through Oc. 27. It will conclude with the test at 6 p.m. on Nov. 3 at AHS. There will be a meeting for all officials following the test at 7 p.m.
For more information, call Ron Metcalfe at (970) 630-8016 or Doug Smith at (970) 768-1914.


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Anti-Obama texts traced to activist
A Virginia-based communications firm has denied wrongdoing — but not responsibility — for a spate of unsolicited anti-Obama text messages that hit hundreds of cellphones Tuesday.
The Internet domains tied to the texting campaign were masked during the text flurry, but on Wednesday GoDaddy.Com unmasked them, suspended them for "spam and abuse," and revealed that the owner is ccAdvertising of Centreville, Va.
Story Continued Below
Early Wednesday, the domain registrant was ccAdvertising COO and failed Virginia state Senate candidate Jason Flanary, but by afternoon the registrant name had been changed to G. Joseph. The CEO of ccAdvertising is Gabriel Joseph III. Both Joseph and his firm have frequently been in the news in connection with questionable advertising practices on behalf of conservative politicians and causes.
The anonymous texts were sent from email addresses, rather than other phones — a loophole in spamming and autodialing laws that the FCC is considering closing. All political communications, however, are required to include a declaration identifying who paid for or approved the message.
Neither Flanary nor Joseph returned calls seeking comment on Wednesday, but a man answering the phone at ccAdvertising referred POLITICO to a statement on the company's website, saying that "is all you're going to get."
"In the more than 12 years since its founding and currently, ccAdvertising has scrupulously complied with all laws and regulations affecting its activities," according to the unsigned statement. "It appears that statements currently being made about ccAdvertising are largely motivated by partisan political considerations."
The firm's website lists clients including Grover Norquist's powerhouse advocacy group Americans for Tax Reform, as well as Sen. Roy Blunt (R-Mo.) and Rep. Kay Granger, (R-Texas). CcAdvertising has also worked with McDonald's and Burger King, according to the client list.
The company has posted a letter of praise on its site from Quest Fore Inc. Chairman Ken Cuccinelli, father of Virginia Attorney General Ken Cuccinelli II, a GOP candidate for governor next year.
The Romney campaign distanced itself from the controversy. "We have nothing to do with these texts and we don't know where they're coming from," Romney spokeswoman Andrea Saul told POLITICO.
Many of the messages, which violated FEC regulations because they didn't include information on their origins, were vitriolic. They included attacks on President Barack Obama related to his support of gay marriage, abortion rights and Planned Parenthood.


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Saturday Show.
All aboard and welcome to episode 12 of Stephanie's Train Travels. This show is all about the amazing adventures that Stephanie has experienced during her career with Amtrak Train Services. Over the years Stephanie has met many amazing people, seen amazing things, and she is full of wonderful stories she eager to share.
We hope you enjoy these wonderful tales. Thank you so much for listening
Listen, Enjoy, and Share.
To Download the show as an MP3 File. Right-Click Where is says "Download" and choose the Save-As option.
(*Disclaimer: This show is not associated with Amtrak and our goal is to share the positive side of cross country travel and all the great people Stephanie has met and adventures she has had. Thank you again).
Podcast: Play in new window | Download


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Definition from Nolo's Plain-English Law Dictionary
A plea entered by a defendant in a criminal case. Often erroneously confused with a claim of innocence, technically a plea of not guilty simply compels the prosecution to prove every element of the offense beyond a reasonable doubt. When the jury (or a judge sitting without a jury) acquits a defendant after trial, they return a verdict of "not guilty," which indicates their conclusion that the prosecution did not meet its burden of proving guilt beyond a reasonable doubt. (See also: reasonable doubt)


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HBO's happy band of brothers are about to drive their caddy convertible off into the sunset.
"Entourage," the sitcom that follows the misadventures of Jersey boy actor Vincent Chase and his inner circle in Los Angeles' high powered movie scene, will end its eight-year run in 2011, reports the New York Daily News. The series will conclude with an abbreviated run next summer.
"We'll do a shorter order to finish up, said Michael Lombardo, the network's programming president.
However, fans of the Drama, E and Turtle shouldn't get down just yet: the show may live on with a big screen movie.
Lombardo said that the show's creator, Doug Ellin "clearly wants to write the film. But he also wants to do it when the storytelling makes sense. So he is clearly thinking about how the [TV] show will end."
The show's snappy patter, celebrity-studded episodes and larger than life capers have earned it both popular and critical praise. It's also served as a showcase for Jeremy Piven's portrayal of volatile and profane super agent Ari Gold, who is based on Ari Emanuel, the brother of White House Chief of Staff Rahm Emanuel.


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S&C's System VI Switchgear combines the innovations of Vista UDS with the versatility of S&C Metal-Enclosed Switchgear, in a space-saving, multi-section package. System VI presents an exciting new option for applications through 34.5 kV requiring 16-kA symmetrical short-circuit duty. Vista gear includes 600-ampere load-interrupter switches and fault interrupters, sealed in an SF6-insulated, elbow-connected tank. Using air-insulated bushings on one or both sides of the tank, multiple Vista units can be joined together or to metal-enclosed switchgear modules such as air-insulated metering bays.
System VI Switchgear's operating controls are separated from elbows and cables — just one operator can safely and easily check the status of switches and perform routine tasks without cable handling or exposure to medium voltage.
Contact: Steven A. Strand
Phone Extension: 2430
E-Mail: [email protected]
Release Date: March 1, 2002


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Tuesday, December 01, 2009
Brian Schneider now a Phillie, will Halladay be next?
Roy Halladay is still in the news for possibly coming to Philly. Although there has been no reason to believe that any deal would be made for him by Ruben Amaro. Halladay has named several teams he would like to be on, and the Phillies are one of them. What would the Phillies have to give up to get him? That would be where it gets interesting. Who would Toronto want? One thing is for sure, J.P. Riccardi is no longer calling the moves for Toronto as GM, but the fact remains who would the Phillies part with to get Halladay and would they want to add a pitcher like him for possibly one season? Halladay also said he wouldn't mind being a Yankee, or with the Red Sox so they may make a move for him as well. It's almost like it's more of who will give Halladay the best deal and if it's ok with Toronto and they get what they want, it will be a done deal with some contending team. I just don't sense that the Phillies are all that strong on acquiring Halladay but stranger things have happened.
Stay tuned for what happens next with the Halladay sweepstakes and listen to the next Phillies Talk podcast that will be posted on this website on Wednesday night! We're taking questions and your comments for the show as well, call 609-829-3125 on our message line to be part of the show! This week's question: Who would you give up for Roy Halladay and why - or should we even think about getting Halladay?
2 comments:
Not sure if it would be worth it to give up the prospects to get Halladay. But I ask these two questions and just think how different your answer is...1) Will the Phillies win the World Series this year with the staff they have? 2) Will the Phillies win the World Series with Halladay, Lee, Hamels, and Happ? There's my answer. I doubt it happens though.ReplyDelete
The odds are against them to win in '10 - that is for sure. I don't really like that they weren't more aggressive than they were in the World Series, it almost seemed like they played very nonchalant at times in the World Series.ReplyDelete
I wouldn't have started Pedro in Game 6 - that was not the right move, but hindsight is 20/20 and the Phillies lost last year, will they win next year? They have 162 games to play to get into the playoffs again. We'll see.


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Skinny Fit Stretch Jeans
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RICHMOND, Va. – Virginia Commonwealth University has named former Georgia State standout Martin Stiegwardt an assistant tennis coach. Stiegwardt will provide instruction to both the Rams men's and women's squads.
Prior to joining VCU, Stiegwardt was the Executive Director of Tennis at SportsQuest Tennis Academy in Richmond, while also serving as Tennis Pro and Junior Academy Director at Willow Oaks Country Club.
"We're very excited to add Martin to our coaching staff," said VCU Head Men's and Women's Tennis Coach Paul Kostin. "He has succeeded at every level throughout his career and his experience will be a great addition to our program here at VCU."
Stiegwardt played parts of his first two collegiate seasons at the University of Florida (2003-04) before transferring to Georgia State (2005-07). As a senior, the Quito, Ecuador native was the Panthers' No. 1 singles and doubles player and led the team to the 2007 Colonial Athletic Association championship, where he was named the tournament's Most Outstanding Performer. That same year, Stiegwardt was part of the highest team ranking in school history (No. 33), while also holding the program's best-ever singles and doubles rankings.
During his prep days, Stiegwardt ranked as high as No. 40 in singles and No. 24 in doubles by the International Tennis Federation. In addition to playing in the Davis Cup in 2002, he competed in Wimbledon and Roland Garos junior events and was the national singles and doubles champion in the Under-12, 14, 16 and 18 age groups in Ecuador.
Stiegwardt, who was named to the Athletic Director's Honor Roll while receiving the CAA Commissioner's Award during his final two seasons at Georgia State, graduated in 2007 with a bachelor's degree in Business Management.


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|Serve over brown basmati rice.
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Brienne Tarth
Brienne of Tarth
Brienne depiction by quickreaver, FFG©
The Maid of Tarth
Brienne the Beauty
Brienne the Blue
House Tarth
Catelyn Tully
Rainbow Guard
A Clash of Kings (Appears)
A Storm of Swords (Appears)
A Feast for Crows (POV)
A Dance with Dragons (Appears)
|Played by
|Gwendoline Christie
|TV series
|Season 2 | Season 3
Brienne, the Maid of Tarth, sometimes mockingly called Brienne the Beauty, is the only child and heir of Lord Selwyn Tarth of Evenfall.
Character and Appearance
Brienne is distinctly unfeminine in appearance, and is considered extremely unattractive by Westerosi standards. She is very tall, muscular, flat-chested and ungainly, with straw-colored hair and broad, coarse features that are covered in freckles. Her teeth are prominent and crooked, her mouth is wide, her lips are swollen, and her nose has been broken more than once. Despite her overall ugliness, Jaime Lannister notices that her large blue eyes are surprisingly pretty and shine with confidence in battle.
When asked about her height, Martin commented:
Brienne is well over six feet tall, but not close to seven, no. Just off the top of my head, I would say Brienne is taller than Renly and Jaime and significantly heavier than either, but nowhere near the size of Gregor Clegane, who is the true giant in the series. Shorter than Hodor and the Greatjon, maybe a bit shorter than the Hound, maybe roughly the same height as Robert.[1]
Brienne has spent most of her life as the object of scorn, rejection and – at best – pity. When she tried to dress and act like a proper lady, she was met with mockery and disdain for her unattractive appearance and lack of feminine social graces; when she turned to a career more suited to her talents as a warrior, she received only contempt and resentment for her gender despite her considerable skill. Perhaps because of this background, Brienne is as awkward in personality as she is in appearance; Catelyn Stark notices that she has none of the easy confidence of some other warrior women, like Dacey Mormont. She yearns for respect and acceptance from others, and easily gives her love and loyalty to the few people who treat her with any degree of genuine courtesy. Renly Baratheon, Catelyn Stark and Jaime Lannister are among those who have won Brienne's friendship and service in this manner.
She can be headstrong and judgmental, but she is also honest, straightforward, loyal and determined. Although she has received extremely poor treatment from most knights, Brienne clings to a naïvely idealized concept of knighthood. Despite – or perhaps because of – the fact that she has no expectation of ever being recognized by society for her accomplishments and strength of character, she nevertheless strives to live up to the ideal of a true knight at all times.
Brienne was born the eldest daughter of Lord Selwyn Tarth, lord of Evenfall Hall, on the island of Tarth. Her mother died when she was so young that she doesn't remember her.[2] She had a single older brother, Galladon, who drowned when she was eight, and two younger sisters, both of whom died in the cradle. This makes her the only offspring of Lord Selwyn, a fact that naturally encouraged him to find a suitable match for her. Given her ugly and ungainly appearance and attitude, however, the task was a difficult one, especially since Brienne was bent on a martial life rather than a marital one, more comfortable with a sword than in the company of court society. She was tutored by a master-at-arms named Ser Goodwin.
Her father successfully found three men willing to betroth her, for her father's wealthy lands, though the first two fell through.[3] The last, Ser Humfrey Wagstaff, warned her he would insist she act womanly once they were wed. Though only sixteen, Brienne replied she would only accept such a demand from a man who could beat her in combat. In the effort, Ser Humfrey ended up with three broken bones and a broken betrothal. After that, Lord Selwyn stopped trying to arrange a marriage for her.[4] Brienne's only positive encounter with a man occurred when the Tarths' liege lord, Renly Baratheon, visited their island during his coming of age tour. He crossed paths with Brienne and treated her courteously, so she fell in love with him.[3] Some time later, Lord Selwyn sent her to Storm's End. [5]
Recent Events
A Clash of Kings
When Renly Baratheon declared himself king at Highgarden, Brienne joined him in his march to King's Landing. In Renly's camp, Brienne is continuously mocked. Some of the young knights wager on who will be the first to get her maidenhead, until Lord Randyll Tarly puts an end to it, warning Brienne that her very presence is the cause of the problem.[6] Later in the march, Brienne proved her mettle with a morningstar in a great melee of 116 knights at Bitterbridge, defeating the Knight of Flowers as well as many of her mocking suitors. She asked to join the Rainbow Guard as her prize, becoming Brienne the Blue. She sharply reminded Catelyn Stark of the courtesy due a king, and was later dismayed when Renly denied the need for an escort for a stroll after the night's feast.[7]
At Renly's parley with his brother Stannis at the Siege of Storm's End (299), Brienne was his standard-bearer. After the negotiations failed, she was assigned to do the same in the upcoming clash, riding in the van alongside Loras Tyrell.[8] The next day at dawn, she was arming the king for battle against his brother when a shadow entered his tent and killed him. She was accused of the murder, but Catelyn Stark was able to convince those present that she was innocent and took Brienne with her when she fled the camp.[9] When they arrived at Riverrun, Brienne wanted to leave to take revenge on Stannis for Renly's death, but Catelyn convinced Brienne to enter her service instead.[10] Brienne is present when Lady Stark speaks with the Kingslayer in his cell, and grants Catelyn her sword when it is asked for.[11]
A Storm of Swords
At Riverrun, after receiving news that her sons Bran and Rickon were killed, Catelyn decided to free Jaime Lannister, making Brienne escort him on his way to King's Landing to fulfill the promise made by the Hand, Tyrion Lannister, to return her daughters Sansa and Arya if the Kingslayer were freed.[12] Brienne defended Jaime ably, and learned much of his history that is little known to Westeros at large and the two developed a grudging respect for each other. They made for the city by boat and threw off pursuit from Riverrun when Brienne scaled a cliff and rolled boulders onto Ser Robin Ryger's pursuing galley[13] and continued by land[14]. After an ambush by outlaws killed their companion, Jaime's cousin Cleos Frey, Jaime tried to escape, dueling Brienne. Manacled and out of practice, Jaime couldn't manage to beat Brienne, who was holding his head underwater when they were captured by the Brave Companions.[15] The unscrupulous sellswords chop off Jaime's sword hand, which swings against Brienne's breasts as it hangs from the Kingslayer's neck and the two are made to ride face-to-face on the same mount. His fighting ability truly gone, Jaime despaired for his life, but Brienne convinced him to live for revenge. In turn, Jaime prevented Zollo, Rorge and Shagwell, three of the Companions, from raping Brienne. At Harrenhal, the two shared a bath and several tales including The Wildfire Plot which Jaime revealed to Brienne. Lord Roose Bolton sent Jaime on his way, but kept Brienne as Vargo Hoat's prize. Jaime, however, soon returned and rescued her.
After their arrival in the capitol, the pair were confronted by Loras Tyrell, who still believed Brienne guilty of Renly's regicide. Jaime had Brienne arrested for her own protection, and arranged for Loras to speak to her; this finally dispelled Brienne's blame. After Catelyn's death at the Red Wedding, Jaime entrusted Brienne with the Valyrian steel longsword given to him by his father Tywin, naming it Oathkeeper. He sends her out to seek the vanished Sansa Stark, to fulfill his promise to Lady Catelyn. As Oathkeeper was forged from the metal of Ned Stark's greatsword Ice, Brienne's is using Stark steel to rescue the Stark girl. Along with this, Jaime gives her two bags full of coin, a mail hauberk, a Lothston shield, and a letter signed by King Tommen saying that she is on a royal mission.[16]
A Feast for Crows
Brienne begins her search at Duskendale, where she allows Podrick Payne, the squire of Lady Sansa's husband Tyrion Lannister, to join her quest. She also has her shield repainted to the arms of Ser Duncan the Tall. She thinks of Lady Catelyn and what she had told Brienne of her daughters. She swears to Catelyn's restless shade that she will never stop looking for Sansa:
I will find her, my lady. I will never stop looking. I will give up my life if need be, give up my honour, give up all my dreams, but I will find her. [4]
Her next stop is at Maidenpool, which she only enters with the unwanted aid of Ser Hyle Hunt, one of the knights who had mockingly courted her in Renly's camp. There she finds Lord Randyll Tarly dispensing justice; he begrudgingly allows her to continue her search. At a tavern she meets Nimble Dick Crabb, who leads her after "a fool" (whom she believes is Dontos Hollard, who might have Sansa with him).
Traveling through Crackclaw Point, the trio arrive at the Whispers, the ruined hall of Nimble Dick's ancestors, encountering a band of Brave Companions remnants led by the fool, who is actually Shagwell, the psychotic jester. Shagwell kills Nimble Dick. Using Oathkeeper, Brienne manages to kill Pyg and Timeon, and forces Shagwell to dig a grave for Dick; she kills him as well when he turns on her. After the fight Hyle Hunt joins her party, having followed her from Maidenpool. [17]
Following the sellswords' information, Brienne heads back to the Riverlands to find Sandor Clegane, who was reported to be with a girl, unbeknownst to her to be the wrong daughter. At Maidenpool they join with Meribald, an itinerant septon, who accompanies them to Saltpans. From there she visits the nearby Quiet Isle, where the Elder Brother assures her that the Hound is dead.
At a crossroads near the Trident, Brienne fights another group of Brave Companions led by Rorge, who has been masquerading as Sandor while raping and murdering in the Riverlands. Brienne kills Rorge, but is grievously wounded by Biter, who chews the flesh off her cheek.[18] After Gendry rescues her from Biter, he and the remaining members of the Brotherhood Without Banners take her captive. The undead Catelyn Stark, now leading the Brotherhood as "Lady Stoneheart", does not believe Brienne's tale of her search for Sansa and judges her to be a traitor who is serving the Lannisters. Brienne was given the choice of killing Jaime Lannister to prove her loyalty, or to hang. Brienne refuses to choose and is sentenced to hang. After seeing Podrick Payne hanging near her, she shouts a single unknown word as they are about to do the same to her[19]
A Dance with Dragons
Brienne appears briefly at Pennytree when Jaime camps there, whatever word she shouted apparently making the Brotherhood spare her. She asks Jaime to help her save Sansa Stark from the Hound, claiming they are a day's ride away. She tells Jaime, however, that he must go with her alone, or the Hound will kill Sansa.[20] The scenario she describes, however, seems unlikely to be real, as Sansa was last seen by readers in the Vale and the Hound is apparently dead.[19]
Family tree
There is widespread speculation that Brienne descends from Ser Duncan the Tall. A shield bearing his personal arms was in the armory at Evenfall Hall, and Brienne later used these arms when she was traveling in the Riverlands.[4] Though Martin confirmed that a descendant of Dunk appeared in the books he did not give a name.[21][22] See Brienne of Tarth/Theories
References and Notes
- ↑ The Citadel. "Brienne of Tarth."y (January 31, 2001) So Spake Martin
- ↑ Game of Thrones, Season 2, "The Ghost of Harrenhal".
- ↑ 3.0 3.1 A Feast for Crows, Chapter 4, Brienne I.
- ↑ 4.0 4.1 4.2 A Feast for Crows, Chapter 9, Brienne II.
- ↑ A Clash of Kings, Chapter 42, Davos II.
- ↑ A Feast for Crows, Chapter 14, Brienne III.
- ↑ A Clash of Kings, Chapter 22, Catelyn II.
- ↑ A Clash of Kings, Chapter 31, Catelyn III.
- ↑ A Clash of Kings, Chapter 33, Catelyn IV.
- ↑ A Clash of Kings, Chapter 39, Catelyn V.
- ↑ A Clash of Kings, Chapter 55, Catelyn VII.
- ↑ A Storm of Swords, Chapter 2, Catelyn I.
- ↑ A Storm of Swords, Chapter 1, Jaime I.
- ↑ A Storm of Swords, Chapter 11, Jaime II.
- ↑ A Storm of Swords, Chapter 21, Jaime III.
- ↑ A Storm of Swords, Chapter 72, Jaime IX.
- ↑ A Feast for Crows, Chapter 20, Brienne IV.
- ↑ A Feast for Crows, Chapter 37, Brienne VII.
- ↑ 19.0 19.1 A Feast for Crows, Chapter 41, Alayne II.
- ↑ A Dance with Dragons, Chapter 48, Jaime I.
- ↑ Summary of the Dayton signing tour with question and answers on the So Spoke Martin section of Website Westeros.
- ↑ Summary of the Mysterious Galaxy Signing in San Diego, California on the So Spake Martin section of website Westeros.
This page uses content from the English Wikipedia. The original content was at Characters from A Song of Ice and Fire. The list of authors can be seen in the page history of Characters from A Song of Ice and Fire. As with A Wiki of Ice and Fire, the content of Wikipedia is available under the Creative Commons Attribution-ShareAlike License.
See also


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Include a title, date and description. When you are done you will be able to tag
it with additional information.
"We have been thrilled with our mobile app and its capabilities! Not only is it tailored to arts organizations, but it is constantly being updated to include the latest technological features. We also love the At-The-Event feature, and our patrons enjoy this 'behind-the-scenes' experience while they are at the theater. 5 Stars!"


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Groups and families with a desire to take in even more of our vibrant city choose the luxurious Executive Suite with its unforgettable skyline and river views. For the quintessential Bangkok experience, inside and out, look no further.
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Time: Bangkok is 7 hours ahead of GMT.


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Five U.S. Cities Where the Poor Can't Get Rich
Americans living below the poverty line have less than a 10% chance of making it into the top tier of earners, according to a recent study. MarketWatch's Rex Crum discusses the five U.S. cities with the lowest chances for upward economic mobility. (Photo: AP)
This transcript has been automatically generated and may not be 100% accurate.
I ... the American dream has always been that no matter what your background if you work hard to get an education that you can end up doing better than parents ... over for people in poverty the question remains is the American dream that ... I'm Rex Crum for MarketWatch ... recently twenty four seven Wall Street took a look at some data about poverty in the United States and some of the cities where if you're born into poverty it's almost impossible to rise out from ... coming in fifth place is the CEO offered Alabama with the upward mobility rate is just three point six percent ... and the high school dropout rate from two thousand to two thousand one was two point five percent than in the twenty fifth most in the country ... but offers Everest scores from fourth to eighth graders in math and reading our concern among the worst nationwide come in fourth place is Columbus Georgia ... the percentage of families led by its single mothers it's pretty High its thirty one point two percent making it the tenth highest in the country ... and only an estimated one in thirty children born in Columbus ... the death of the top twenty percent of income earners as adults ... that was held up by Greenville Mississippi ... of the staggering high amount of families with a single mothers forty three point three percent the highest rate of of households with some others in the country ... of achieving green bill are seen struggling to perform well in school students in grades three through eight ... scored lower than all other large metropolitan areas both reading and math stay in the state of Mississippi here for the Number two city Alyssa's city of Clarksville ... percent of families with sumo is also very high the third highest in the country thirty five point six percent ... and Ashley seventeen point four percent of children born in Clarksville were born to teenage mothers during the period of uncertainty and topping the list the city was the worst economic mobility for American ... children born in the party is Memphis Tennessee ... I just two point six percent of children raised in the bottom twenty percent of the economic groups there are expected to rise to the top group ... more than thirty two percent of children in Memphis area growth in homes with single