text:
Leukotriene modulators
Adrenergic β2 receptor agonists
Muscarinic receptor antagonists
Therapeutic Overview
Asthma is a chronic inflammatory disorder of the large airways in which many different cellular elements play a role. A characteristic feature of asthma is obstruction of the airways (predominantly in the third to seventh generation of the bronchi) that is reversible with time or in response to treatment. Even when patients have a normal airflow (which for mild asthmatics is much of the time), their lungs are hyper-reactive to a variety of stimuli that occur naturally (e.g., cold air, exercise, chemical fumes) or are used to test pulmonary function (e.g., methacholine, histamine, cold air). Bronchial hyper-reactivitycorrelates with inflammation of the bronchi, which includes damage to the epithelium and eosinophil infiltration. Other characteristics of asthma include airway mucosal edema, mucus hypersecretion, and remodeling of the airways. Symptomatically, patients experience chest tightness, wheezing, shortness of breath, or coughing. Mild forms of the disease occur in up to 10% of the population, but asthma requiring regular treatment affects approximately 2% of the population.
Compared with asthma, chronic obstructive pulmonary disease (COPD) is defined by the Global Initiative on Obstructive Lung Disease as "A disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles and gases." COPD includes chronic obstructive bronchiolitis with fibrosis and obstruction of small airways, emphysema with enlargement of airspaces and destruction of lung parenchyma, loss of lung elasticity, and closure of small airways. Most patients with COPD experience a triad of symptoms, including:
• Chronic obstruction
• Emphysema
• Mucus plugging
Leukotriene B receptor
Cyclic adenosine monophosphate
Central nervous system
Chronic obstructive pulmonary disease
Forced expiratory volume in 1 second (liters)
Immunoglobulin type E
Leukotriene modulators
Metered-dose inhaler
Peak expiratory flow
Tumor necrosis factor
Smoking is by far the primary cause of COPD; other risk factors include occupational dust and chemical exposures, environmental exposure (second-hand smoke), and genetic predisposition (primarily α1antitrypsin deficiency). Currently, COPD is the fourth leading cause of death in the United States.
Normal bronchial smooth muscle tone is controlled by vagal innervation (see Chapter 9). Cholinergic activity or sensitivity is often increased in asthmatics, and increased cholinergic tone is the primary reversible component of COPD. However, most patients with asthma also have increased adrenergic activity (see Chapter 11), which manifests as increased wheezing if patients are treated with β adrenergic receptor blocking drugs (e.g., propranolol), which are contraindicated in asthma. A variety of agents can contribute to the inflammation of asthma; however, immediate hypersensitivity to common allergens is the most common cause. It is estimated that 80% of children and 50% of adults with asthma are allergic. The common allergens include seasonal outdoor allergens (e.g., ragweed pollen, grass pollen, and mold) or the year-round indoor allergens (dust mites, cockroaches, and domestic animal dander). Allergens cause release of the preformed granule mediator histamine, which can trigger bronchospasm. However, antihistamines (H1 receptor antagonists) are relatively ineffective in the treatment of asthma, demonstrating that other factors are key mediators of the asthma attack. In patients with asthma, in addition to the release of prestored mediators such as histamine from mast cells, other inflammatory mediators are synthesized and released including arachidonic acid, its metabolites, and several cytokines (Fig. 16-1). Leukotrienes (LTs), primarily LTD4, are implicated as major mediators of bronchoconstriction. Agents that inhibit the synthesis or action of the LTs, known as leukotriene modulators (LTMs), are useful for the treatment of asthma.
FIGURE 16–1 Mast cells release prestored inflammatory mediators such as histamine, which act rapidly. Other mediators such as leukotrienes are newly generated after their precursors are released and act more slowly. Some mediators are also produced by basophils.TNF-α, Tumor necrosis factor-alpha; IL-4, Interleukin-4.
The inflammatory component of COPD differs from that of asthmatics in that patients with COPD demonstrate increased neutrophil as opposed to eosinophil activity. In COPD, macrophage activation, due to exposure to noxious stimuli, releases neutrophil chemotactic factors, including interleukin-8 and LTB4. Protease enzymes are also released that destroy connective tissues in the lung parenchyma, and oxidants capable of direct tissue damage are produced. These events lead to the pathological damage to small airways and increased mucus secretion characteristic of COPD. The resulting chronic inflammation causes fibrosis and a proliferation of smooth muscle. As the airways progressively narrow, airflow is severely limited, and respiratory function declines.
Asthma is treated using three main approaches. The first is avoidance of the causative factors, when possible, particularly for patients sensitive to indoor allergens. The second is the use of antiinflammatory drugs, including cromolyn and related agents, glucocorticoids (GCs) (see Chapter 39), and LTMs. If used regularly, these drugs can reduce the signs and symptoms of bronchial hyperactivity, characteristic of asthma. Third, drugs that can reverse or inhibit the development of bronchoconstriction are important; these compounds include methylxanthines, epinephrine (Epi) and selective adrenergic β2 receptor agonists (see Chapter 11), and the muscarinic receptor antagonists (see Chapter 10).
The current therapeutic approaches for the treatment of COPD are similar to those for asthmatics with three exceptions. First, the cessation of smoking is essential to prevent development of COPD and to slow its progression. Second, of the antiinflammatory drugs, only GCs are currently used in the treatment of acute exacerbations of COPD; long-term use of these compounds for the management of COPD is not recommended. Third, β2 receptor agonists are used as bronchodilators for patients with COPD, and muscarinic antagonists result in further improvement. Therefore the combination of a β2-agonist and a muscarinic receptor antagonist is useful in COPD.
The goals in treatment of pulmonary disease are to reverse acute episodes, control recurrent episodes, and reduce bronchial inflammation and associated hyper-reactivity. Three general considerations must be kept in mind:
• The inhaled route of drug administration is very important and has special requirements.
• The pharmacokinetics of pulmonary drugs are based primarily on lung-function response; blood concentrations can be important for the methylxanthines because of toxicity concerns.
• The most commonly encountered adverse effects of respiratory medications are the short-term side effects of the methylxanthines and the cumulative side effects of orally administered GCs.
Because many patients use inhaled steroids or β2 receptor agonists chronically, the adverse effects of these drugs, which are relatively infrequent when used acutely, become more important. A summary of the therapeutic considerations for the treatment of asthma and COPD is presented in the Therapeutic Overview Box.
Therapeutic Overview
Antiinflammatory Agents
Cromolyn and related agents control mediator release from mast and other cells and for their generalized membrane-stabilizing effects
Glucocorticoids, inhaled or systemic, for controlling transcription of mediator genes, and for controlling edema, mucus production, and eosinophil infiltration
Leukotriene modulators to decrease inflammatory mediator synthesis or antagonize inflammatory mediator receptors
Methylxanthines for reducing the frequency of recurrent bronchospasm
Adrenergic β2 receptor agonists for relaxing bronchial smooth muscle and decreasing microvascular permeability
Muscarinic receptor antagonists for inhibiting the bronchoconstrictor effects of endogenous acetylcholine
Mechanisms of Action
Treatment of asthma and COPD involves the use of drugs with mechanisms that affect different aspects of these diseases. Table 16-1 summarizes these drugs and their mechanisms of action.
TABLE 16–1 Mechanisms of Action of Drugs to Treat Asthma and COPD
Beneficial Effect
Drug Class
Cellular Mechanisms
Decreased inflammation
Prevent the release of inflammatory mediators
Alter chloride ion channel function
Glucocorticoids (GCs)
Regulate gene expression
Leukotriene modulators (LTMs)
Decrease leukotriene (LT) synthesis or prevent LT receptor activation
Prevent activation of histamine receptors
Increase cAMP
Adenosine receptor antagonist
Adrenergic β2 receptor agonists
Increase cAMP
Muscarinic antagonists
Block activation of muscarinic receptors by endogenous acetylcholine
Chromones (Cromolyn and Nedocromil)
Cromolyn is a synthetic substance derived from a natural plant product that has several important actions. Cromolyn was originally shown to inhibit the release of histamine from mast cells in vitro. Subsequently, it was demonstrated that inhaled cromolyn could inhibit exercise-induced bronchospasm, progressively decrease bronchial hyperactivity, and inhibit seasonal rises in bronchial hyperactivity in patients allergic to grass pollen. Cromolyn and nedocromil act at the surface of the mast cell and eosinophils to inhibit Ca++ influx, thereby preventing the release of histamine and other inflammatory mediators. Cromolyn and nedocromil are active on the lung only when given by the inhaled route. They have no direct bronchodilator effect and thus are not useful for treating acute asthma attacks.
The GCs have multiple actions that decrease inflammation in asthma, which is key to improving asthmatic symptoms and preventing exacerbations. In controlling the inflammation of asthma, the primary effect of the GCs is to alter gene expression. The GCs, through activation of GC receptors (see Chapter 39), suppress the expression of genes for many inflammatory proteins. Inflammation is mediated by the increased expression of multiple inflammatory proteins including cytokines, chemokines, adhesion molecules, and inflammatory enzymes and receptors. The expression of most of these inflammatory proteins is regulated by increased gene transcription, which is controlled by proinflammatory transcription factors. The GCs are believed to switch off only inflammatory genes and do not suppress all activated genes because of the selective binding to coactivators that are activated by proinflammatory transcription factors.
In addition to suppressing the synthesis of inflammatory mediators, the GCs also induce the transcription of several antiinflammatory proteins, including lipocortin, neural endopeptidase, and inhibitors of plasminogen activator. Lipocortin inhibits the activity of phospholipase A2, thus decreasing the release of free arachidonic acid from phospholipids and reducing the subsequent production of leukotrienes and prostaglandins.
GCs decrease bone marrow production of eosinophils and enhance their removal from the circulation by mediating their adherence to capillary walls (margination). GCs also reduce the local accumulation of eosinophils by inhibiting the release of eosinophil chemotactic factors such as LTB4 and cytokine tumor necrosis factor-α (TNF-α). The effect of the GCs on neutrophils is opposite to that on eosinophils. By inhibiting margination and stimulating bone marrow production, GCs lead to an increase in circulating neutrophils.
Leukotriene Modulators
The LTs are potent inflammatory mediators generated from the metabolism of arachidonic acid through the 5-lipoxygenase (5-LOX) pathway (Fig. 16-2). These compounds, along with prostaglandins and related compounds, belong to a group of substances termed the eicosanoids (see Chapter 15). The LTs are synthesized in many inflammatory cells in the respiratory system including eosinophils, mast cells, macrophages, and basophils and are responsible for mediating numerous asthmatic symptoms via stimulation of specific LT receptors. LTB4 is a potent neutrophil chemotactic agent whose actions result from stimulation of members of the LTB receptor (BLT) family. Similarly, LTC4 and LTD4 cause bronchoconstriction, mucus hypersecretion, and mucosal edema and increase bronchial reactivity through activation of the Cys-leukotriene (CysLT, formerly known as the LTD4) receptor family. The effects of the LTs can be modulated either by inhibiting LT biosynthesis or by blocking activation of CysLT receptors. Zileuton* is an inhibitor of 5-LOX, thereby decreasing LT synthesis, whereas zafirlukast and montelukast are antagonists at Cys-LT1 receptors, thereby blocking receptor activation. These drugs are less effective antiinflammatory agents than the corticosteroids, but are preferable to long-term GC therapy because they have fewer adverse effects (see Chapter 39). They are used prophylactically in combination products.
FIGURE 16–2 Newly generated lipid mast cell mediators depicting the sites of action of the LTMs. Zileuton* inhibits 5-lipoxygenase, thereby inhibiting the synthesis of the leukotrienes, whereas zafirlukast and montelukast are antagonists at the CysLT1 receptor. The inhibitory actions of the LTMs are shown in red.
Theophylline is a methylxanthine, pharmacologically similar to caffeine found in coffee and cola drinks. Theophylline exerts three actions, which may contribute to its usefulness as a bronchodilator. A major action of theophylline is as an adenosine receptor antagonist in bronchial smooth muscle. Adenosine acts as a natural bronchoconstrictor and increases histamine release from lung mast cells. Blocking these actions of endogenous adenosine could contribute to the antiinflammatory action of theophylline. The second action is theophylline inhibition of phosphodiesterase (PDE), increasing levels of cyclic adenosine monophosphate (cAMP), which lead to bronchodilation; however, the clinical significance of this mechanism has been questioned, because concentrations of theophylline required to inhibit this enzyme exceed those achieved with usual doses. The third proposed mechanism of theophylline involves its ability to activate histone deacetylase, an enzyme that functions to inhibit the acetylation of core histones required for the transcription of inflammatory genes. The ability of the methylxanthines to interact with ryanodine receptors to increase Ca++ mobilization is important for the ability of these agents to enhance skeletal muscle strength, but not to their action in asthma.
Adrenergic β2 Receptor Agonists
Stimulation of adrenergic β2 receptors raises cAMP concentrations and inhibits smooth muscle contraction (see Chapter 9). Physiologically, bronchial smooth muscle relaxes, and the release of some mast cell-derived bronchoconstricting substances is inhibited. In addition, these drugs decrease microvascular permeability and suppress parasympathetic ganglionic activity (see Chapter 10). There is no evidence for an antiinflammatory effect of adrenergic agents or for any beneficial effect on bronchial hyperactivity.
Several β2 receptor agonists have been used therapeutically for the treatment of asthma. Epi and isoproterenol are highly effective but are reserved for special circumstances because of their nonselective activity, leading to β1 receptor-mediated cardiac stimulation. Short-acting selective β2 receptor agonists include albuterol,1 terbutaline, metaproterenol, bitolterol, and pirbuterol. Formoterol and salmeterol have been developed as highly lipid-soluble long-acting agents (t1/2 = 12 hours).
Muscarinic Receptor Antagonists
Bronchial smooth muscle is innervated mainly by the parasympathetic nervous system, and its activation causes bronchoconstriction (see Chapter 9). Before the development of modern pharmacology, leaves from the belladonna plant, which contain muscarinic antagonists (atropine and scopolamine) were smoked as a treatment for asthma. Atropine can be used as a bronchodilator and to reduce secretions, but its use is limited by autonomic and central nervous system (CNS) adverse effects. Ipratropium bromide is a quaternary nitrogen derivative of atropine that does not cross the blood-brain barrier but competitively inhibits muscarinic acetylcholine receptors in bronchial smooth muscle (see Chapter 10). Ipratropium is used as an inhaled preparation. Tiotropium is a long-acting muscarinic antagonist used as a bronchodilator that is useful for patients with COPD.
Anti-immunoglobulin Antibody
Omalizumab is a recombinant monoclonal antibody, which binds to and neutralizes human serum immunoglobulin type E (IgE) and prevents allergens from activating mast cells and other cells that release cytokines (see Chapter 6).
The pharmacokinetics of the drugs used for the treatment of asthma are complicated as a consequence of the routes of absorption and differences in the rates of response. Blood levels are relevant only for theophylline and related methylxanthines because of the relatively low therapeutic index and high incidence of adverse effects of these agents. Therefore mean pulmonary function response times are generally used as an indicator of pharmacokinetic profiles. Response rates vary significantly from patient to patient, presumably reflecting differences in the specific pathological state of the obstruction in the lung.
Both cromolyn and nedocromil act on inflammatory cells and neurons in the bronchial epithelium and are active only when inhaled, rendering plasma levels largely irrelevant. Cromolyn is very poorly absorbed from the gastrointestinal (GI) tract and has few systemic side effects because it is rapidly excreted. Although cromolyn has no direct bronchodilator activity and should not be used to treat an acute attack, it can be used to control exercise-induced bronchospasm, if administered 10 to 15 minutes before the onset of physical activity. In contrast to its rapid effect in controlling exercise-induced bronchospasm, long-term treatment with cromolyn or nedocromil requires several days or even weeks to produce an optimal antiinflammatory effect.
The pharmacokinetics for the GCs are presented in Chapter 39. When used for the treatment of asthma or COPD, responses to inhaled or oral steroids can occur within 4 hours but may take as long as 2 weeks, depending on the nature of the underlying lung disorder.
Leukotriene Modulators
The LT receptor antagonists, montelukast and zafirlukast, as well as the 5-LOX inhibitor zileuton* are all orally administered, which is advantageous for treatment of children and other patients who have difficulty with or are noncompliant with inhaled therapies. Zileuton* has the disadvantage of requiring dosing four times per day. Montelukast and zafirlukast have similar pharmacokinetic profiles and may be administered once (montelukast) or twice (zafirlukast) daily. Zileuton* is also an inhibitor of hepatic CYP3A and will lead to increased levels of drugs metabolized by this CYP variant, including theophylline. This drug-drug interaction increases potential toxicity if the two drugs are administered concurrently.
Theophylline clearance is influenced by food, smoking, age, disease, and other drugs metabolized by the liver (Table 16-2). Monitoring serum theophylline concentrations is necessary for any patient taking more than a minimal dose orally, especially sustained-release formulations, because of the multiple factors that influence blood concentrations and because the range of safe therapeutic concentrations is narrow. The therapeutic range is 5 to 15 µg/mL, and serious toxicity is increasingly likely at blood concentrations greater than 20 µg/mL, which results in a low therapeutic index.
TABLE 16–2 Factors influencing Blood Concentrations of Theophylline
When administered intravenously, theophylline can act rapidly on the lungs as a bronchodilator. However, this requires large bolus doses, which are used only occasionally because of toxicity. It is easier to maintain therapeutic blood concentrations by the oral route using sustained-release preparations, but this approach can lead to problems of cumulative toxicity.
Adrenergic β2 Receptor Agonists
A general comparison of the pharmacokinetic profiles for these compounds is presented in Table 16-3. The bronchodilation that occurs in response to inhaled β2 receptor agonists has a fairly consistent onset at 5 to 30 minutes. Tightness of the chest will abate in most patients with asthma within 10 minutes after an injection of Epi. An optimal effect usually occurs within an hour and may last for 2 to 4 hours. In most circumstances β2 receptor agonists are effective for approximately 4 to 6 hours. Prolonged, repeated use of short-acting β2 receptor agonists, however, can cause a significant increase in heart rate in a small proportion of patients as a result of systemic absorption and concomitant stimulation of cardiac β1 receptors. With the development of a longer-acting β2 receptor agonist (salmeterol), which lasts for more than 12 hours, this problem may be partially resolved. However, unlike the short-acting β receptor agonists, salmeterol is not effective in treating acute episodes. Its major uses are in controlling nocturnal asthma and some cases of exercise-induced bronchospasm. The use of salmeterol alone has been associated with an increased risk of severe asthma exacerbations. Therefore it has been recommended that this agent be taken in fixed-dose combinations with an inhaled corticosteroid.
TABLE 16–3 Comparison of the Pharmacokinetics of Adrenergic β2 Receptor Agonists and Muscarinic Receptor Antagonists
Muscarinic Receptor Antagonists
Inhaled ipratropium bromide is poorly absorbed and has few systemic side effects. The peak bronchodilator effect occurs 1 to 2 hours after inhalation, with a duration of action of 3 to 5 hours (see Table 16-3). Tiotropium, which exhibits selectivity at M1 and M3 receptors (see Chapter 10), has a duration of action of 24 hours. Both of these agents are used for management of the bronchoconstrictive component of COPD.
Relationship of Mechanisms of Action to Clinical Response
The central problem in managing asthma is that the symptoms range from occasional tightness in the chest after exercise (which may require no treatment) to continuous airway obstruction. Assessment of pulmonary function by spirometry (to measure forced expiratory volume [FEV1]) or a portable peak flow meter (to measure peak expiratory flow [PEF]) is essential to monitor baseline pulmonary function, correlate changes in airway obstruction with symptoms, and determine the patient's response to treatment. The patient should be encouraged to record peak flow values for a 2-week period to establish a baseline, assess the severity of episodes, and determine his or her individual response to treatment. An FEV1 or a PEF less than 80% of the predicted value is considered a mild obstructive episode. The predicted value is determined from the patient's age, gender, race, and height, based on a healthy population. Alternatively, the patient's best recorded PEF baseline value can be used as the predicted value. An FEV1 or PEF less than 60% of predicted values indicates moderate obstruction, and an FEV1 or PEF less than 40% of predicted values indicates severe obstruction. Most patients will show a 15% to 20% increase in FEV1 or PEF 15 to 20 minutes after administration by metered dose inhaler (MDI) of a bronchodilator, such as a β2 agonist or a muscarinic antagonist. Less than a 12% increase indicates inadequate acute bronchodilator response, and further treatment will be necessary.
Reduced allergen exposure, inhaled cromolyn Na+ or nedocromil, inhaled GCs, or oral LTMs are antiinflammatory treatments that are each capable of reducing bronchial hyperactivity to help manage the problem. Cromolyn and related agents are used prophylactically only and are most effective for treating extrinsic asthma in children and young adults as well as exercise-induced bronchospasm.
Although the mechanism of the therapeutic effect of the methylxanthines in asthma is not clear, regular treatment can be very effective in controlling symptoms. The methylxanthines prevent episodes of airway obstruction. Theophylline administered IV is active within minutes, but when taken orally, 1 to 2 hours are required before its effects occur. Its duration of action depends on absorption and metabolism but correlates well with blood concentrations.
Systemic GCs are the most effective treatment for both moderately severe and severe asthma and are used for treatment of acute exacerbations of COPD. However, these compounds lead to development of side effects after chronic administration (Chapter 39). The indication for oral corticosteroids is ongoing airway obstruction that is not relieved by other medicines within 1 to 2 days. Only a very small percentage of asthmatics (0.1%) become dependent on steroids, but this may represent as many as 10 patients per 100,000; thus it is a very important cause of iatrogenic disease.
For acute severe episodes, corticosteroids such as methylprednisolone may be administered IV. Although the GCs have no direct bronchodilator effects, and 6 hours are required to achieve maximal effects, peripheral blood eosinophil counts decline within 2 hours, and significant effects on lung function and symptoms can be observed within 4 hours of systemic administration. Thus the early use of systemic steroids has become a mainstay of treatment in the management of acute asthma and COPD, both in outpatient practice and in the hospital. In some cases, high doses of inhaled steroids can be used to abort an attack. However, in severe cases, mucus impaction and poor ventilation of the lungs prevent the effective delivery of inhaled steroids, and, therefore oral or IV administration is urgently required.
Outpatient Treatment of Asthma
In a patient with occasional wheezing, a diagnosis must be established by demonstrating a reversible airway obstruction and having the patient use a peak-flow meter at home for 2 weeks. Treatment involves using a β2 receptor agonist, two puffs by MDI when necessary. In a patient with exercise-induced bronchospasm, it is imperative to show that breathlessness after exercise is associated with airway obstruction. Recommended treatments to prevent exercise-induced bronchospasm are an inhaled β2 receptor agonist, two puffs 5 to 10 minutes before exercise, or two puffs of cromolyn Na+ by MDI 10 to 20 minutes before exercise, or one puff of salmeterol by MDI 30 to 60 minutes before exercise. Inadequate control requires identifying the causes of the bronchial hyperactivity. Leukotriene antagonists are effective as prophylactic agents.
In a patient who is suffering more frequent symptoms, including nocturnal asthma, or who is using a short-acting β2 receptor agonist more than three times per week, documentation of reversible airway obstruction is of paramount importance. This can be achieved by: (a) measuring changes in PEF or FEV1 before and after administration of the bronchodilator; (b) demonstrating a 15% to 20% increase in PEF or FEV1 after bronchodilator administration; or (c) demonstrating hyper-reactivity to inhaled histamine, methacholine, or cold air. Skin tests should be used to identify relevant sensitivities to allergens. If a patient has positive skin test results, then education relevant to decreasing exposure to the specific allergens is a first step in management. These patients may benefit from the combination of a long-acting β2 receptor agonist, in combination with a leukotriene antagonist. Short-acting bronchodilators should be reserved for the reversal of acute episodes.
Inhaled corticosteroids, cromolyn, or nedocromil, taken on a regular basis, should be prescribed for any patient who continues to have symptoms necessitating bronchodilator therapy more than three times weekly. If symptoms persist and spirometry confirms obstruction, the dose of the antiinflammatory agent should be increased, and an oral delayed-release theophylline preparation, 200 to 300 mg two or three times a day, should be considered. After 4 days the theophylline blood concentrations should be from 5 to 14 µg/mL.
For acute asthmatic episodes, doses of inhaled steroids should be increased to four puffs four times a day and theophylline added as needed. A short course of oral steroids (60 mg of prednisone reduced to zero over 6 to 8 days) may also be necessary. In the clinic or emergency room, a nebulized β2 receptor agonist is the first line of treatment, which can be repeated three times at 20-minute intervals, and then hourly thereafter. Patients not responding to nebulizer treatment should receive steroids (60 mg of prednisone or 125 mg of methylprednisolone IV).
Patients with unresponsive persistent symptoms may be treated with regular-dose, inhaled steroids four puffs four times a day, theophylline up to a maximum therapeutic range, and additional drugs, including cromolyn or nedocromil, a β2 receptor agonist delivered by nebulizer, or an LTM. Courses of oral steroids (6 to 30 days) and other agents may also be considered. The physician should reinforce education on allergen avoidance and consider other factors such as diet, fungal infections, drug reactions, sinusitis, and gastroesophageal reflux.
Antihistamines are generally not recommended for treatment of asthma. However, many allergic patients with rhinitis and asthma use antihistamines with no apparent harmful effects. Sedative antihistamines (see Chapter 14) should not be used in patients with acute bronchospasm. Antibiotics are commonly recommended for management of an exacerbation of asthma because of sputum production but should be reserved for those patients with bronchial infiltrates, fever, or sinusitis.
Allergen Avoidance
Exposure to allergens, particularly those found indoors, is well recognized as an important cause of asthma. Identification of sensitivity and education about measures necessary to decrease exposure are an important part of antiinflammatory treatment. For control of dust mites, enclosing the mattress and pillows in dust mite-proof covers, washing all bedding in boiling H2O, removing carpets, and using air filtration systems are important measures. Removing cats or dogs from the environment may be helpful; however, it will take weeks or months for the associated allergen levels to decrease. Cockroach eradication may be important for inner-city homes, in particular, and should involve such measures as enclosing all food, sealing gaps around pipes, and using poisonous bait. Special issues related to asthma are discussed in Box 16-1.
BOX 16–1 Special Issues
Asthma in Young Children
There are special issues concerning side effects and the delivery of antiasthmatic drugs in children. Children can be treated with a nebulizer and face mask from infancy; by age 7, they can usually use an MDI with a spacer. Inhaled cromolyn is the antiinflammatory drug of choice because it has no serious side effects and is available for use in a nebulizer. In young children, total daily doses of inhaled steroids as low as 400 μg have been reported to reduce growth. Long-term oral theophylline treatment (taken as sprinkles on food) is effective and well tolerated in many children. However, hyperactivity and/or learning difficulties are potential problems. Allergen avoidance should be recommended for any child who requires more than occasional treatment and has positive skin test results.
Asthma in Pregnancy
Management of asthma in pregnancy is similar to that for adults. Risks of uncontrolled asthma to the fetus outweigh the possible risks of drug therapy. Inhaled cromolyn and related agents, inhaled steroids, β2 receptor agonists, delayed-release theophylline, antibiotics for sinusitis associated with asthma, and short courses of steroids are given in normal adult doses.
A reactive airway often develops in patients with COPD as their disease progresses. Although these patients are generally not allergic, drug treatment of this condition has many features in common with asthma treatment in adults. Thus theophylline, β2 receptor agonists, steroids, and nebulized cromolyn are commonly used. Special issues include O2 supplementation and monitoring blood gases in respiratory compromised patients. Responses to muscarinic receptor antagonists in patients with COPD are better than with β2 receptor agonists, whereas the converse is true in asthmatics.
Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity
The side effects of drugs used with asthma are summarized in the Clinical Problems Box.
The side effects of cromolyn and nedocromil are restricted to the irritant effects of inhaling the drugs. There is very little convincing evidence for short-term or long-term drug toxicity and no recognized blood concentration that is toxic. Occasional cases of dermatitis, gastroenteritis, and myositis that are apparently associated with cromolyn use have been reported but are very unusual.
The side effects of systemic corticosteroids are discussed in Chapter 39 and are mentioned here briefly in the context of pulmonary disease. The most important issue is the difference between short- and long-term use. Treatment with high-dose steroids, even short-term, can cause hypertension, diabetes, GI bleeding, and CNS disturbances. Elevations in blood glucose concentration and emotional changes are common but are usually easy to manage. Long-term steroid use produces a wide range of severe side effects, including thinning of the skin (striae, bruising), osteoporosis with rib fractures and vertebral compression, aseptic necrosis of the femoral head, which usually presents with pain, diabetes with complications, GI discomfort, ulceration and bleeding, cataract formation, and CNS disturbances, including frank psychosis. Prolonged oral use of steroids causes profound suppression of adrenal function. If patients are taking oral steroids for more than 7 days, the dose should be gradually reduced, because abrupt withdrawal can result in life-threatening adrenal insufficiency. Patients must be made fully aware of the harmful effects of long-term orally administered steroids.
Although there was concern that inhaled steroids would produce serious side effects in the lungs or systemically, this is not the case. The major side effects of inhaled steroids (e.g., beclomethasone dipropionate) have been oral candidiasis and occasionally irritation triggered by the use of an MDI. In all patients, but especially those with COPD, yeast infection of the mouth (thrush) is common and requires local treatment. The efficacy of chronic use of inhaled steroids in patients with COPD is not well established, because the possibility exists that inhaled steroids might encourage fungal colonization in patients with a severe fixed obstruction, that is, FEV1 <40% predicted.
In contrast, large doses of inhaled corticosteroids have significant effects on the adrenal axis and bone growth in children. Inhaled steroids are all active locally, and their systemic side effects depend on both absorption and metabolism. There is some evidence that budesonide and flunisolide have fewer systemic effects because their metabolites are inactive.
Leukotriene Modulators
Adverse effects of the leukotriene antagonists zafirlukast and montelukast are minimal, and generally, the drugs are well tolerated. However, rare cases of hepatotoxicity and eosinophilic vasculitis have occurred. The clinical features of the vasculitis are consistent with Churg-Strauss syndrome, a life-threatening condition typically treated with systemic corticosteroid therapy. The occurrence of the vasculitis syndrome appears to be linked with the decrease or withdrawal of oral corticosteroid therapy. Therefore the patient and the physician need to be acutely aware of symptoms related to eosinophilia, vasculitic rash, worsening of pulmonary symptoms, cardiac complications, and developing neuropathies.
Zileuton* can produce elevated liver enzymes, typically in the first few months of therapy. It also inhibits hepatic CYP3A, which metabolizes many drugs, including theophylline. Considering the correlation of serum levels of theophylline to therapeutic and toxic effects, patient monitoring is necessary if the two drugs are used concurrently.
The most common side effects of theophylline that can occur within the normal therapeutic range are either GI upset (e.g., heartburn, abdominal pain, nausea, vomiting) caused by an increase in gastric acidity or CNS effects including headache, anxiety, tremor, and insomnia (similar to those reported with excess use of caffeine). Side effects occur with concentrations as low as 5 µg/mL but increase greatly in frequency and severity when the blood concentrations of theophylline exceed 15 µg/mL (the recommended upper limit). When blood concentrations exceed 20 µg/mL, seizures and cardiac dysrhythmias are possible and become common when blood concentrations exceed 35 µg/mL. Seizures can result in significant mortality; thus elevated theophylline concentrations are treated as an emergency with gastric lavage, oral charcoal, and even dialysis. Considerable attention has been given to CNS symptoms in children receiving methylxanthines, including poor attention and insomnia, with resultant poor school performance.
Adrenergic β2 Receptor Agonists
The primary side effects of adrenergic agonists are cardiac stimulation, hypertension, tremor, and restlessness (see Chapter 11). The use of selective β2 receptor agonists decreases the risk of some of these effects. Inhaled β2 receptor agonists generally produce fewer side effects than oral preparations. Nonetheless, tachycardia and muscle tremor still occur. Continued use of these agents may result in the desensitization of β receptors (see Chapter 1); however, GC therapy can prevent or partially reverse this phenomenon. Epi can ameliorate severe life-threatening asthma attacks when administered subcutaneously. However, there are very few indications for this form of treatment in older patients or in those with underlying cardiovascular disease. Although there was a concern that chronic use of short-acting β2 receptor agonists would worsen asthma, this has not proven to be the case.
Muscarinic Receptor Antagonists
Inhaled ipratropium or tiotropium may give rise to drying of the mouth and upper airways. Because these drugs are administered via inhalation, systemic adverse effects,
Less potent than steroids; may produce coughing during inhalation
Inhaled Steroids
Low doses induce candidiasis; high doses cause growth retardation and other systemic effects
Oral Steroids
High doses can cause GI problems and CNS disturbances
Leukotriene Antagonists
Rare hepatotoxicity and eosinophilia
Narrow therapeutic index, nausea and vomiting, seizures, cardiac dysrhythmias
Adrenergic β2 Receptor Agonists
Tachycardia, tremors
Muscarinic Antagonists
Dry mouth
such as those associated with atropine, are unusual (see Chapter 10).
New Horizons
Cilomilast is a PDE type 4 antagonist under investigation for the treatment of respiratory inflammatory diseases. PDE-4 regulates cell function by altering intracellular levels of CAMP and cyclic guanine monophosphate, particularly in inflammatory cells associated with asthma and COPD. Cilomilast may be less likely to cause CNS or GI side effects and fewer drug-drug interactions.
Etanercept is a [TNF-α] antagonist, being investigated in asthma treatment. TNF-α is a proinflammatory cytokine that is potentially important in refractory asthma. Etanercept is a fusion protein produced by recombinant DNA technology that is approved by the U.S. Food and Drug administration for the treatment of rheumatoid and psoriatic arthritis and ankylosing spondylitis. Initial studies indicate that enteracept improves lung function and airway hyper-responsiveness in asthma.
LTB4 is a proinflammatory lipid mediator generated from arachidonic acid through the action of 5-LOX that is implicated in many inflammatory disorders including asthma. BLT1, a G-protein-coupled receptor, is specific for LTB4, and the LTB4-BLT1 pathway is a novel future target for the treatment of asthma. Different immunosuppressive treatments, including methotrexate and tacrolimus, have been used in patients with severe or steroid-dependent asthma with variable degrees of success. Epidemiological evidence indicates an association of severity of asthma with fungus infections, and treatment with systemic antifungals (fluconazole or itraconazole, see Chapter 50) may be helpful for asthma in some cases.
(In addition to generic and fixed-combination preparations, the following trade-named materials are some of the important compounds available in the United States.)
Adrenergic β2 Receptor Agonists
Albuterol* (AccuNeb, Proventil, Ventolin)
Bitolterol (Tornalate)
Metaproterenol (Alupent, Metaprel)
Pirbuterol (Maxair)
Terbutaline (Brethine, Brethaire, Bricanyl)
Formoterol† (Foradil, Aerolizer, Perforomist)
Salmeterol† (Serevent)
Cromolyn‡ (Intal, NasalCrom)
Nedocromil (Alocril, Tilade)
Inhaled Glucocorticoids
Beclomethasone (Beclovent, Beconase, Quar, Vancenase, Vanceril)
Budesonide (Entocrot, Rhinocort, Pulmicort)
Flunisolide (AeroBid, Nasalide, Nasarel)
Fluticasone (Cutivate, Flonase, Flovent, Veramyst)
Triamcinolone acetonide (Azmacort)
Leukotriene Modulators
Montelukast (Singulair)
Zafirlukast (Accolate)
Muscarinic Receptor Antagonists
Ipratropium (Atrovent, Atrovent HFA)
Tiotropium (Spiriva)
Oxtriphylline (Choledyl)
Theophylline (Slo-bid, Slo-Phyllin, Uniphyl, Theo-24, Theo-Dur)
* In the United Kingdom and Japan the drug name is salbutamol.
† Long-acting agents not suitable for emergency use. The use of these agents has been recommended to be taken only in fixed-dose combinations with an inhaled corticosteroid to avoid increased risk of severe asthma exacerbations with one of these agents alone.
‡ In the United Kingdom the drug name is sodium cromoglycate; in Japan the drug name is cromoglycate sodium.
Acetylcholine (ACh) is synthesized and secreted by non-neuronal cells and modifies their behavior. This "non-neuronal cholinergic system" is present in airway inflammatory cells where ACh has both proinflammatory and antiinflammatory activity, depending on the cell type. The function of this system can be modified by nicotine in cigarette smoke, the inflammation of asthma and COPD, and the drugs used in treating these diseases.
Certain gene polymorphisms in patients with asthma can influence responses to β2 receptor agonists, GCs, and LTMs. These mutations result in altered responses to therapy, GC resistance, decreased theophylline clearance and toxicity, and increased bronchoconstriction.
Anonymous. Drugs for allergic disorders. Treat Guidel Med Lett. 2007;60:71-80.
Anonymous. Drugs for asthma. Treat Guidel Med Lett. 2005;3:33-38.
Morrow T. Implications of pharmacogenomics in the current and future treatment of asthma. J Manag Care Pharm. 2007;13:497-505.
Weiss et al. 2006 Weiss ST, Litonjua AA, Lange C, et al. Overview of the pharmacogenetics of asthma treatment. Pharmacogenomics J. 2006;6:311-326.
1. An 11-year-old child experiences wheezing and difficulty breathing when exercising. Which of the following drugs would be recommended to prevent these symptoms?
A. Albuterol
B. Cromolyn
C. Fluticasone
D. Ipratropium
E. Zafirlukast
2. A 74-year-old patient with a 50-year history of smoking presents to the emergency room with an acute exacerbation of his COPD. Which of the following classes of drugs would be most effective at relieving the bronchoconstrictive component of his disease?
A. Muscarinic antagonists
B. Corticosteroids
C. Leukotriene modulators
D. Oxygen
E. Adrenergic β2 receptor agonists
3. An essential component in the treatment and management of pulmonary disease is control of the inflammatory process. Which of the following agents will reduce the recruitment of eosinophils?
A. Albuterol
B. Flunisolide
C. Ipratropium
D. Nedocromil
E. Zafirlukast
4. The short duration of action of inhaled β2 agonists can be problematic, especially for nocturnal asthma. Of the following inhaled β2 agonist bronchodilators, which exhibits a long half-life that can ameliorate the problem?
A. Albuterol
B. Metaproterenol
C. Salmeterol
D. Bitolterol
* This drug is no longer available in the United States.
1 In the United Kingdom and Japan the drug name is salbutamol.


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All Seasons at Victor Harbor 48676
House, Victor Harbor
Rated 5 out of 5 stars 2 reviews
Confirmation within 24hr
From $281 per night {{quote.pricing.message}} Total {{quote.pricing.price | format:'currency':'short'}} for
Min 2 - 7 nights stay
Enjoy the waves, relax & watch the world pass by, Views as far the eyes can see.
Amazing fantastic spectacular that describe the incredible sea, sand, city & island uninterrupted panoramic views that this property offers.
What is included
Full use of this unique house -
This delightful two storey home situated in the prestigious Adare. Only a two minute walk to the beach & only a minute drive or short walk the main shopping precinct.
The entry hall will take you to the slate tiled kitchen with separate dining area. Then on to the large lounge with sensational sea and island views.
Move out on to the tiled balcony for even better views.
Take the corridor to the master bedroom with bathroom access & the second bedroom is here as well. All bedrooms with built-in robes.
Downstairs you will find two bedrooms, family room with access to second balcony. Rumpus room & separate bathroom. The laundry leads out to the secluded terrace/garden area. Perfect for reading that great book or entertaining the family.
Bedroom Configuration:
Main Level
1. Queen Bed with direct access to bathroom
2. Queen Bed
3. Queen Bed with direct access to bathroom
4. Queen Beds, Three Singles, One Trundle Bed
Quilts, pillows, & mattress protectors are supplied for all beds. Guests are asked to bring your own linen, however we can arrange linen for you at an additional cost. You don't have to decide right now, we can help you right up to a few days before you arrive in relation to this issue.
Kitchen is fully equipped with a full sized fridge/freezer, wall oven, ceramic cooktop, crockery, platters, bowls, cutlery & yes the steak knives are included, pots pans, electric toaster, kettle, microwave oven, two drawer dishwasher, sandwich toaster/grill press, hot water urn, food warmer, juice machine....
Full sized laundry, front load washing machine, clothes dryer, an outside clothes line, iron & ironing board, full size laundry tub. In addition to the upstairs fridge/freezer there is a 180L chest freezer available to use.
Outside you can enjoy the outdoor under cover entertaining area with a six burner BBQ with side burner, outdoor table furniture with umbrella or move to the front deck.
Eco Friendly house solar panels and solar hot water systems, Reverse cycle air-conditioning, Two LED colour TV's DVD/CD player, X-Box console with games, Soccer table, Other games including board games for the whole family to enjoy.
PLEASE NOTE: If you are planning on partying then is NOT the house for you,
There is a strict NO PARTY policy. The house is located in a residential area and public disturbances will not be tolerated, our neighbours will report issues such as excessive noise or uncontrollable barking from pets. Guests will be asked to leave the premises without notice should noise or nuisance complaints be received or if the number of guests exceeds the number at time of booking.
Sorry No Smoking inside the house, Strictly No Pets.
Security Bond is Payable.
Check In is at 2pm on the day of Arrival
Check Out is at 10am - Weekends & Long Weekends stays may have a later checkout
but must be confirmed with owner.
What to bring:
All you need is
- your happy family & friends
- what you plan to eat
- your drinks
- a range of clothing temperature varies a bit on the seafront, even in Summer
- your personal toiletries
The house should be left neat & tidy as per when you moved in, any extra cleaning required to return the house to original condition will be deducted from the bond.
$2500.00 per week = December/January
$1500.00 per week = February/March/November
$1500.00 4 nights = Easter
$1500.00 per week = Holidays
$ 975.00 Long Weekends
$1200.00 per week = Off peak
$ 275.00 Nightly minimum two nights
Full Linen Hire $180.00 if required
Victor Harbor is a short one hour drive from Adelaide. The property is only minutes from the town centre. It is the perfect holiday destination for those wishing to escape from city life. Enjoy sitting back either inside or outside this beautiful house taking in the magnificent land/sea views. You can spend your days reading, fishing, walking/cycling the many trails, surfing, day trips to Cape Jervis, Port Elliot, Middleton, Goolwa, McLaren Vale exploring or just taking in the beautiful views.
Things to do/Attractions:
The Victor Farmers Market is held every Saturday Morning - 8:00am to 12:30pm
Numerous golf courses near by including Victor Harbor, McCracken & South Lakes,
South Australian Whale Centre
Catch the Cockle Train from Victor Harbor to Goolwa
Catch the Horse Tram to Granite Island to see a fairy penguin
Port Elliott for surfing or stop off at the best bakery on the coast
Port Elliott Antique & homeware
Goolwa where you can book cruise down the Murray River to the Corrong & Murray Mouth, Suits all boating activities, sailing, canoeing, jet skiing, fishing/leisure cruising,
boat ramps
Walking/Hiking Trails
Hire a bike or BYO to get around and follow the bike tracks along the coast
There are numerous cafes, wineries and shops to explore during your stay.
Rating snapshot
Average customer ratings
No reviews have been submitted for this property.
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Have a question?
Feel free to send a message to the owner/manager if you have any specific needs, or if you require additional information before you can commit to a booking request.
Select request booking to access the quote calculator and to check availability.
Enter your check in and check out dates to see availability and a total price.
|Sun to Thurs ($ p/n avg.)
|Fri & Sat night
|7 night stay
|Min night stay
|Extra adult ($ p/n)
|Extra child ($ p/n)
|{{tariff.weekdayMinimumRate | format:'currency':'short'}} -
|{{tariff.weekendRate | format:'currency':'short'}} -
|{{tariff.weeklyRate | format:'currency':'short'}} -
|{{tariff.extraAdultCost | format:'currency':'short'}} -
|{{tariff.extraChildCost | format:'currency':'short'}} -
The following dates have a special rate or exception applied. Please note any discounts applicable to these dates will still apply.
|{{exception.priceInCents / 100 | format:'currency':'short'}} p/n
|Security Deposit
|{{rates.bond | format:'currency':'short'}} p/s
|{{extra.valueInCents /100 | format:'currency':'short'}} p/n p/p p/np p/s
|Yes No
p/n = per night, p/s = per stay, p/p = per person, p/np = per night and person. Ask the owner to arrange optional extras
Note: Pricing is subject to change, and a minimum stay period and other conditions may apply. You should confirm pricing with the property owner.
Prices listed based on 12 adults. Property has 8 beds and can sleep a maximum 12 people.
- Available
- Unavailable


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Tags#bonfireufm #UFM almonds apple snow artofpuddings art of puddings baking biscuit Bonfire Night Bramleys butter cake Christmas baking cooking apples damson damson cobbler Damson Day damson gin damson gin shots damsons damson sauce damson wine desserts figs foodie event frangipan jam jams jellies jelly kilburn lemon zest Lyth valley msmarmitelover pudding of the month puddings Queens Park Day seasonal fruit tart Tart It Up! Transition Town Kensal to Kilburn underground night market vanilla cheesecake Westmoreland Damson Association Winster valley Witherslack
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Autumn fruit crumble
There's nothing more comforting, as the nights draw in, than a crumble made with the last of the blackberries combined with Turkish figs and this season's bramley apples. You can be inventive with your fruit combinations. I just happened to … Continue reading
Posted in Baking, Desserts, Fruit, Pudding of the Month, Puddings Tagged almonds, apples, autumn pudding, blackberries, Bramleys, crumble, figs, hazelnuts, lemon zest, Natoora, Tim's Dairy, Turkish figs 2 Comments
Queens Park Day: 11th Sept
Art of Puddings came to Queens Park Day last Sunday and a fantastic day was had by all. We sold everything we brought along!! 300 dessert shots, Vanilla Cheesecake, redcurrant jelly, damson jam, damson cheese, plum jam & gooseberry jam, … Continue reading
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The Company previously had received a notice from the staff of Nasdaq that the staff was recommending the delisting of the Companys common stock. Pursuant to that notice (which was previously filed with the SEC on form 8-K) the Company requested a hearing on the delisting recommendation, which hearing was held on November 10, 2016. On December 21, 2016, the Company received a letter from the Hearing Panel stating that the Company securities will be suspended from trading effective at the opening of business on December 23, 2016. The Hearing Panel determined that the Company delisting is pursuant to listing rule 5101 and 5250(a)(1).
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
Date: December 21, 2016
John Power
John Power
Chief Financial Officer
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Other recent filings from the company include the following:
Notification of inability to timely file Form 10-Q or 10-QSB - Nov. 14, 2017


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- Mr.Graves "28 Reasons You're Better Off Neve..."
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Response to 29 Signs You Grew Up Playing Little League:
I question whether or not the kid in #5 touched home plate. It's not the best angle, but he maybe touches the corner before stepping over and sliding into nothingness. This is why we need instant replay. It's Matt Holliday in the 2007 National League Wild Card tie-breaker game all over again!!


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The Almyra, Cyprus, is a sleek, minimalistic hotel in a prime spot on the shoreline of Pathos. Tour operator Sovereign Luxury Travel is offering a 20% early booking discount, as well as complimentary half-board, a free child place and an online discount, plus - exclusively to Sovereign customers - a £150 January Sale discount, an upgrade to a sea-view room and a €50 spa credit per booking. The special-price seven-night holiday departs on 22 May 2013, and costs £2,399 - saving up to £1,481 - for a family of three, including all accommodation on a half-board basis, return flights from Gatwick Airport and private transfers. Various other family holidays have been discounted in the Sovereign Sale Event, with complimentary treats, upgrades and savings of up to 45% to be had on holidays booked before 31 January 2013.
To book contact Sovereign Luxury Travel (0844 415 1936; www.sovereign.com)
Families of three can save £900 on six-night stays at the Constance Lemuria in the Seychelles over Christmas. Based on two adults and one child sharing a suite on a bed-and-breakfast basis, the offer costs from £2,725 per adult and £855 per child, and includes return flights from London Heathrow as well as private transfers. The resort, situated on Anse Kerlan beach on the island of Praslin, has the Seychelles' only 18-hole golf course. The offer is valid for Christmas week (20-27 December 2012).
To book contact Western Oriental (0207 666 1234; www.westernoriental.com)
With the start of the ski season comes the recent renovation of the Chalet Bois de Bay in Verbier, Switzerland, which is now offering total savings of £2,154 when booked with VIP SKI. The chalet sleeps 10, and is a few steps away from the Médran liftpass. Staff take care of off-piste responsibilities such as breakfast, afternoon tea and a three-course dinner every day. The deal, which applies throughout the season, means that the eight person of the group goes free, and the ninth and tenth guests pay half price.
To book contact VIP Chalets (0844 557 3119; www.vip-chalets.com)
From 2 January until 28 February 2013, the Sample NYC Winter Sale gives discounts on room rates and other deals. The Signature Collection Third Night promotion offers a free third night at certain top hotels; NYC Restaurant Week (14 January-8February 2013) promotes three-course prix-fixe menus at leading restaurants, and two-for-one theatre tickets will be available during Broadway Week (22 January-7 February 2013).
For more information or to book contact NYC GO (www.nycogo.com/wintersale)
Puri Ganesha, a collection of four thatched villas on Bali's comparatively undiscovered north-west coast, is celebrating its 15th anniversary with a sale: five nights for the price of four, or seven nights for the price of six, when booked before 15 December 2012. One-bedroom pool villas, from US$550 per night, are set in an acre of ocean-facing garden and come with two staff members. Guests are also provided with a daily-changing menu of organic dishes, prepared by resort owner and Cordon Bleu-trained chef, Diana von Cranach. The raw-food expert also hosts cookery workshops for guests keen to learn how they can heal their bodies through healthy eating.
To book contact Puri Ganesha (www.puriganesha.com)
Virgin Atlantic is offering savings of up to £298 per person on three-night holidays at the world-famous Atlantis, The Palm resort in Dubai. Two adults sharing a standard room can expect to pay a reduced £1,099 per person for three nights, including direct flights with Virgin Atlantic from Heathrow. Prices are based on departures on 14 January 2013.
To book contact Virgin Holidays (0844 557 3870; www.virginholidays.co.uk)
Luxury coastal bolthole The Tide House in St Ives, Cornwall, is offering 15% discounts on three-night breaks between now and 22 December 2012. The snug, six-bedroom hotel is believed to be the oldest in St Ives, but has recently been renovated in tasteful, nautical-chic style. A three-night stay in a double room (based on two sharing) costs from £146 per person, and includes breakfast, plus a complimentary bottle of champagne upon arrival.
To book contact The Tide house (www.thetidehouse.co.uk)
The dramatic cityscape of Kuala Lumpur will play host to a motoring spectacle in March, 2013: the Formula One Malaysia Grand Prix. Premier Holidays are offering fans of the sport savings of £165 per person on a four-night stay at the Parkroyal Kuala Lumpur that includes Hill stand tickets for the practice day, qualifying and the big race, as well as return flights from London Heathrow with Malaysia Airlines. The package must be booked by 31st December 2012 and is valid for travel on the 20th March 2013.
To book contact Premier Holidays (08444 937 542; www.premierholidays.co.uk)
The Danish flair for design shines through at the recently renovated Ibsens Hotel in Copenhagen, where guests will receive 30% off a 3-night stay in January 2013. The hotel's stylishly retro aesthetic suitably sums up all that makes the Danish capital cool, and the central lakeside location in Nansensgade makes shopping for Sarah Lund-style sweaters an easy undertaking. The three-night package from i-escape.com costs £181 (£90 per person).
To book contact i-escape.com (www.i-escape.com)
A seven-night stay at the Kempinski Hotel Soma Bay in Egypt will save couples more than 15% if they book a seven-night holiday with Classic Collection. The resort sits on the Red Sea, a superb spot for those keen on diving or snorkelling in the resort's own colourful reef. Two adults sharing a double/twin lagoon-view room will pay from £929 per person, a price that includes seven nights' bed-and-breakfast, flights from London Gatwick and private transfers. Trips must be booked by 31 March 2013 and the reduced rates apply to stays between 1 May 2013 and 31 October 2013.
To book contact Classic Collection (0800 008 7299; www.classic-collection.co.uk)
Encounters Travel are celebrating 10,000 Facebook 'likes' by offering fans 10% off all bookings of small-group tours made by 21 December 2012. To get the discount, 'Like' Encounters Travel on Facebook and then quote 'Facebook' when making a booking, for deals on tours to more than 21 destinations, including Kenya, Uganda, Morocco and Nepal.
To book contact Encounters Travel (0800 088 6002; www.encounterstravel.com)
In the spirit of the festive season, London's ultimate botanical institution, Kew Gardens, is offering free entry over the 12 days of Christmas (22 December 2012 - 4 January 2013). There will be 9,000 free tickets for each day of the specified period available online to book from 17 December 2012, and activities at the floral institution include enchanting winter tree tours, a Santa's grotto, a vintage carousel, the David Nash: A Natural Gallery exhibition and a Treetop Walkway with views of London's skyline. Kew Gardens is closed 24-25 December 2012.
To book a free ticket, visit www.kew.org
All prices are correct at the time of publishing.
All offers subject to change and availability.


text:
Crystal sakura-3 -nail-art by ShangovaWatch
©2005-2017 Shangova
Just back from the University - so this is me on the photo actualy. Part of))
Hope you'll enjoy the new nail-art design)
Hope you'll enjoy the new nail-art design)
oh that pretty
Really nice!!
a really beautiful work <3
Wow...it's really beautiful!
very beautiful nails! wow! I just have to try nail art too
Beautiful a little Japenese looking too!! ( Merry Christmas) ( x )


text:
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Retailers interested in stocking any of the European Rail Timetable products should in the first instance contact our Commercial Manager at email@example.com. If you are a customer wishing to order multiple items then please contact us to request a bespoke delivery cost
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RevoStock Clean Moves 550920
After Effects Project \ Commercials \ Intros \ Business \ Simple \ Clean \ Photo Displays
After Effects Project - Clean Moves 550920 by AEtemplates @ RevoStock
After Effects Project \ Commercials \ Intros \ Business \ Simple \ Clean \ Photo Displays
Music: Available on RevoStock; SoundFX: Not Included; Stock Video: Not Included; Replaceable Text Spots: 18; Replaceable Logo Spots: 1; Replaceable Video Spots: 8; Loopable: no; Downloads: 2; Model Release: no.
Clean Moves is created in After Effects CS5 (compatible Cs5 | Cs5.5 | Cs6) in Full HD, 1920x1080
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Insert up to 8 media, 18 text and 1 logo
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ReadMe.pdf with instructions & help included
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Keywords: 3d, slide, abstract, background, sphere, blue, business, color, communication, corporate, digital, display, effects, lights, media, technology, presentation, Company, Commercial, Clean, trailer, moves, showcase, energy, Advert, Advertising, TV, HD, Teaser, Colors, intro, mosaic, mosaik, play, action, fast, speed, sport, elegance, stylish, rock, dynamic, white, globe, geometrix, loop, 30s.


text:
Generation of Pleasure Seekers
- Artist: Chess Club
- Genre: Rock
- Release Date: 8/1/2006
Chess Club is a collective that spans several musical genres and diverse lyrical themes ... The four members of Chess Club produce music that is both aesthetically pleasing as well as intellectually stimulating. The music is carefully planned from lyrical to musical content but never sounds un-spontaneous. Intelligent lyrics and careful musical arrangements are the norm even in the more discordant passages that undeniably make up a fully-realized Chess Club song. Each song contains it's own sometimes obvious and sometimes subtle hook that pulls the listener in and demands their undivided attention. The songs, whether played live or recorded, always leave the listener satisfied but forever wanting more. Chess Club likes to think of each member as an element. Each element has spent considerable time honing his expertise on the respective instruments that make up the band's musical canvas. This is readily apparent in the music as well as the ease and comfort with which they perform live. They are always aware that a truly good band is more than the sum of it's parts. There is a relationship that is formed within this musical collective which allows the elements to simply 'know' where the music is going. Chess Club is a collective that spans several musical genres and diverse lyrical themes; but in the end what they create is simply music.
|Generation of Pleasure Seekers
|Chess Club
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text:
Mr Burnham called the Tory's leader's commitment to the health service into doubt by claiming that he had on "bland protestations of love" for the NHS.
He also warned that a Conservative government would take the NHS backwards by abandoning national targets on patients' waiting times.
The attack threatens to heap further pressure on Mr Cameron after Daniel Hannan, a Conservative MEP, publicly condemned the NHS as a "60-year mistake" on US television.
However, it comes only days after Mr Burnham was ridiculed for claiming in an interview that there were no longer waiting lists on the NHS.
Writing in The Guardian on Tuesday, Mr Burnham highlights three Tory proposals which have created what he describes as "three substantial dividing lines" between the two main parties.
He attacked Conservative plans for a major overhaul of the way the NHS is run by handing day-to-day control to an independent board.
Mr Burnham said: "For a party that has promised a 'bonfire of the quangos', turning Britain's best-loved institution into the biggest quango in the world – responsible for a £100bn budget and 1.4 million staff – is a proposal that has had dangerously little scrutiny to date."
Mr Burnham also condemned Tory plans to scrap Labour's three "flagship" waiting targets – that patients should receive treatment within 18 weeks of a referral by their GP; that all patients should be treated within four hours of arriving at an accident and emergency department; and that cancer patients wait no longer than two weeks to see a specialist.
Mr Burnham said: "This would be a backwards step. Now that these targets have been achieved, Labour will turn them into enforceable rights for patients. Removal of these standards, as the Tories propose, would inevitably see a loss of public accountability and a return to postcode variation."
He also raised concerns that local pay bargaining would be reintroduced by a Tory government, saying: "This would be a mistake. National pay structures bring a stability to the system in terms of recruitment and retention."
Mr Burnham added: "If you dig beneath the bland protestations of love, there is a genuine philosophical difference on the NHS between the political parties.
"It urgently needs to be debated because it will define the kind of NHS we have in 10 years' time."
The article follows calls by Mr Burnham at the weekend for Mr Cameron to withdraw the whip from Mr Hannan and to cancel invitations to US republican politicians to the Conservative Party Conference, who Labour said had "rubbished" the NHS.
In a letter, Mr Burnham said the moves would "reassure the British people that your colleagues' commitment to the NHS is not just skin deep."
Mr Cameron was forced to slap down Mr Hannan, describing his views as "eccentric" and insisting that his party stood "four-square behind the NHS".


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Tuesday, March 1, 2011
Are you ready for this one? One of the famous alternative rock band in the 90s will be rocking the Big Dome for the first time next week as Ovation Productions and STOKED Entertainment presents
"Stone Temple Pilots LIVE in Manila"
When: March 9, 2011
Where: Araneta Coliseum
For tickets, call TICKETNET at 911-5555 or visit www.ticketnet.com.ph for more details
Don't miss it! Buy your tickets now!
Posted by Manila Concerts at 11:51 PM
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Stingers release 2012 schedule
The Willmar Stingers announced their 2012 schedule on Monday.
The Stingers will open their third season against the Mankato MoonDogs 7:05 p.m. May 30 at Bill Taunton Stadium.
The full schedule can be viewed at www.willmar
Changes to the Northwoods League for 2012 include the elimination of the Brainerd Lakes Area team from the league. The Waterloo Bucks will take the Lunkers' spot in the Northwoods League North Division. The Lakeshore Chinooks (Mequon, Wis.) will join the South Division in their inaugural season.


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|22 Jul 2013
How can I diagnose why my copy/paste function stops working??
Good afternoon everyone,
I have developed a curious problem whereby my copy/paste function no longer works. It does not work in any browser, and i cannot even copy and paste into the search box under the start menu. For example, I may be trying to copy a tracking number and paste it into UPS and suddenly the past function will not work. I can highlight the number but it will not past the number. This is just an example. I usually must restart my PC and get it on the initial try and most times it will work that first try but not after.
Any suggestions would be greatly appreciated!!
|My System Specs
|22 Jul 2013
Run SFC /SCANNOW Command - System File Checker.
Are there other performance problems?
Is this the original HP preinstalled WIn7 larded with the worst load of bloatware and duplicate utilties that have better versions built into Win7? Most tech enthusiasts would never run such an install - literally the worst possible install of WIn7 one can have - but instead prefer to Clean Reinstall - Factory OEM Windows 7 to enjoy Win7 native perfect performance.
|My System Specs
|22 Jul 2013
Hi gregrocker,
I ran the SFC/SCANNOW and there were no problems found, and yes, this is the only issue.
Yep, it is the OEM HP Win7.
Computer runs excellent otherwise, even with das' bloatware, lol
I hope reinstalling the OS would be a last resort.....
|My System Specs
|22 Jul 2013
Will copy work using Cntrl C and paste using Cntrl V?
I would at least Clean Up Factory Bloatware
|My System Specs
|22 Jul 2013
Yes, it worked the first time I tried it, but only then. After it worked the first time it will not work again. I would have to restart my PC to get it to work again.
|My System Specs
|22 Jul 2013
Do you use any registry cleaners or system optimizers ?
Have you tried booting in Safe Mode to see if copy/paste works there?
You could try this to clear the clipboard and see if that helps.
Clear Clipboard Shortcut - Create in Windows
|My System Specs
|22 Jul 2013
Yes, i use CCleaner.
In safe mode the copy/paste seemed to work with no problems, I was able to repeatedly copy and paste.
|My System Specs
|22 Jul 2013
You can try a clean startup to see if you can find a startup program that is causing an issue for you.
Troubleshoot Application Conflicts by Performing a Clean Startup
|My System Specs
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Updated in a new second edition, this readable book prepares graduate nursing students to be nurse educators in settings of staff development, patient education, or academia—covering commonalties of teaching that pertain to all three. Practical information and cutting-edge content emphasize the theories and strategies most likely to be used in the field.
Reviewer:Bonnie L. Saucier, PhD, RN(Indiana State University)
Description:This book, designed to help nurses learn how to teach, provides the theory base for nurses who are in an educator role. Included are examples of how the concepts in this book are applied in various work settings.
Purpose:This book addresses the commonalities of teaching across numerous settings. Nurses who teach patients, staff, or students have the opportunity to learn teaching principles applicable to their specific needs. The author's objectives are met.
Audience:Nurses who are in educator roles can use the information in this book to develop an understanding of educational issues and innovations, which include the topics of literacy and distance learning. The author has 30 years of experience as an educator and has brought to the nurse basic learning theory information with many approaches that can assist in achieving desired learning outcomes.
Features:The chapters are divided into three sections. Part I on teaching an learning includes a chapter on "good teaching" and research related to good teaching as well as principles for good practice in teaching. Part II on the learner provides information about patients, students and nurses as learners. Motivation and readiness, multicultural and gender aspects of learning, along with readability and literacy are just a few of the topics found in this section. Part III on teaching strategies incorporates advantages and disadvantages, purposes and uses of methods and research on the strategies. Each chapter includes features that are useful as teaching strategies: case study, critical thinking exercises, and ideas for future research.
Assessment:This book provides a unique and much needed format for new and/or seasoned nurse educators to learn or revisit exciting teaching techniques.


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In the 80s, AT&T urged people—metaphorically—to 'reach out and touch someone' with their telephone service. (A literal suggestion to do so would have been baffling and possibly criminal.) So what did this metaphor of contact evoke exactly, and why was it so effective a tag-line? Telephones have always defied the distances society has created through migration, colonization, and urbanization—a magic that can now seem ordinary. Telephones allow a grandmother to speak to her grandson she has never seen and a daughter to ask her father for college money. Even if only in an illusory or metaphorical sense, a telephone can bring people—the anonymity of a conference call notwithstanding—'closer' together, as if they were in the same room sharing a moment as a family, the subjective space shrinking without regard to the objective distance maintained.
What about today's ubiquitous cell phone? It can be a surreal sight to turn a corner on a street and see a wall of people—without exception—on their cell phones coming toward you. It can be an unsettling sight altogether to see someone shout at a pocket of empty space, before noticing he or she is using a hands-free device. Is everyone speaking to their grandmother or asking for money over long distances? Further, what is the need in society for this immediacy in which the time between statement and response becomes shorter and shorter? People have no conception any longer of correspondence by letter and the anticipation of a reply.
AT&T's campaign was, of course, during the pre-historic time before cell phones, let alone the more literal reach-out-and-touch-your-iPhone interface. It is interesting to note, however, that the encouragement to 'reach out and touch someone' can be regarded now as almost more of an admonition against the very use of the cell phone itself. Stop talking on your cell phone and 'literally' go reach out and touch someone. I once had a professor in an introductory sociology course practically lament the passing of the days of letter-writing and in apocalyptic overtones note how the cell phone was keeping people from speaking face to face any longer. I can remember thinking he was old and 'out of touch'. Flash forward a Ph.D. later and I don't accept text messages and would prefer students just to see me after class.
In a recent issue of the journal Nature it was reported that people using cell phones are predictable in their movement patterns. It turns out that even with the technology to span the globe in search of adventure and still be subjectively near someone at a moment's notice (depending on your willingness to accept roaming charges) we are not going anywhere too far from each other. We like the social routine of contact and known places.
It seems there is a certain ambivalence we feel toward modern technologies upon which the AT&T metaphor was 'touching'. Freud even noted in Civilization and its Discontents that
"If there had been no railway to conquer distances, my child would never have left his native town and I should need no telephone to hear his voice; if traveling across the ocean by ship had not been introduced, my friend would not have embarked on his sea-voyage and I should not need a cable to relieve my anxiety about him."
We use technologies so that we may be closer to those for whom we most care and we use them so that we may keep our distance from those we cannot or will not yet face. It is in this ambivalence that our language and metaphors seek some expression.
The contrast between 'reaching out and touching someone' and reaching out and touching someone reveals something more than simply our use of metaphors or so-called literal language: it reveals who we are as human beings. The kind of psychology necessary to understand us as human beings is one that does not smooth over our paradoxical beliefs and behaviors as if our mind were merely a mirror of a straightforward and less-than-metaphorical nature. Human beings are complicated and psychology ought to be more so than what textbooks present.
In one sense, one can regard language and metaphor as the making publicly observable of one's private observations. It is a blurring of boundaries of sorts. This is a blog by someone whom you have not met. I doubt it will ever prove 'touching' in some overly sentimental sense of that word, but it is certainly true that even though we are no closer to each other than strangers, these words have brought us together for a short while. What language in general and a metaphor like 'reaching out and touching someone' in particular reveals is that—despite our seemingly paradoxical search for personal identity and individuality, as well as our insistence on privacy—we seek each other out. All psychology is inherently and constitutively a social psychology.


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VideoHive Field-Ash Tree With Bright Red Berries 9752480
Stock Footage \ Nature
Berries \ Autumn \ RedRowan \ Branches \ Outdoor \ Nature \ Daylight \ Beautiful
Stock Footage - Field-Ash Tree With Bright Red Berries 9752480 by Renewer @ VideoHive
Stock Footage \ Nature
Rowan tree with naked branches and red berries at autumn day
Alpha Channel: No; Looped Video: No; Frame Rate: 29.97; Resolution: 1920x1080; Video Encoding: Photo JPEG; File Size: 224mb; Number of Clips: 1; Total Clip(s) Length: 0:18.
2 in 1 - Three Syringes on Black Mirror Background; Sunset View of Field With Dry Grass; Field-Ash Tree With Bright Red Berries; Snowdrift With Dry Grass; Quadcopter Drone Flies Over the Field; Briar Berries With Hoarfrost in Frosty Day ; Pouring Tea to Cup From Steel Electric Teapot.
Keywords: autumn, beautiful, berries, close-up, day, daylight, fall, field-ash, fruits, natural, nature, nobody, orchard, outdoor, red.


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Discussion in 'Orlando Hotels and Attractions' started by Sunny37, Mar 31, 2011.
Any advice? Trying to help someone plan their trip and they are on a VERY tight budget.
Check on ebay, you can often find 3 or 4 bedroom homes a few miles from Disney for as little as $75 per night. We were about to book a 4 bedroom 4 bath house for a week in May for $550. However we found a great price on Bonnet Creek and went there instead.
Separate names with a comma.


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Spent just one night here with spouse, but would have love to stay longer! Checked in to room #12, a suite. Sweet it is! Has a separate living room with sofa, desk and tv, and kind bed in the adjacent room. Free wifi, kettle for...More
Getting you more information on this room
Getting you more information on this room
"Room 20 has sloping walls with lots of places to bang your head."


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Every holiday is colorfully represented with gentle pizzazz. Browse our extravagantly expansive array of invaluable seasonal decorations and gifts to fill your home including hallmark decorations and ornaments, seasonal table settings, holiday decorations, seasonal gifts and much more.
Gold and crystal ornaments make ostentatious decoration a breeze. With glamorous elegance, these sparkling sculptures can enhance the holiday spirit with an enchanted glittering sheen. These magnificently bright carvings are perfect for Christmas trees and window booths. There are endless inspired animal creations to choose from, and spiritual symbols are also duly stocked at all times.
Hallmark brings their holiday expertise to the arena with a rich assortment of family friendly gifts. Their personalized mugs are sure to satisfy any close acquaintance. Inscriptions for relatives are mass engraved on these quaint cups. They are perfect for sipping warm tea or steaming coffee by a holiday fire.
Festive headbands are also provided to instill enthusiastic engagement for the holidays. Costume accessories are regularly supplied, and all the equipment for a vivacious Halloween is conveniently compiled in one place. Fluid trick-or-treating is now guaranteed, and Christmas has never been so easy.
Hallmark Red Spatula with Santa Design
Hallmark Santa Hat Wine Stopper
Brand new!
Hallmark Perfectly Pink Bunnies Basket features fabric pink bunny heads in circle to make basket with hot pink handle. 5" x 5" x 9"
Hallmark Bunny with Carrots Basket features fabric carrots with fabric bunny at bottom and green fabric handle. 5.5" x 5.5" x 9"
Halloween Glitter Signs come in Wicked, Boo, Spooky, or Beware in orange or black with ribbon hanger. 9.5" W
Hallmark I Love Dad Mug features white ceramic mug with red interior, candy cane striped handle and reads "I Love Dad," with candy cane striped heart.
Small Feather Spider features spooky black spider made of soft furry feathers. 6.5 x 9 x 3
Hallmark Hoppy Spring Duckling Plush 4.5" x 6" x 4.5"
Hallmark All Ears Bunny Basket features soft white fabric bunny head shaped basket with floppy ears and green handle. 5" x 5" x 8.5"
Christmas Wood Block Message Signs feature holly berry design in corner and each with special Christmas message to choose from. Choose from "Santa Define Good," "Believe," "Santa Stops Here," "Peace Love Joy," "Jesus is the Reason for the Season," "Meet Me Under the Mistletoe," "Merry Christmas," or "Bah-Humbug Scrooge." 3" x 15"
Glass and Metal Jack-O-Lantern Night Light comes in three different styles. Will be sent ONE at random.
Hallmark red and white polka dotted mug with snowman handle
Small Spider on Web comes in black or purple. 1 x 20.5 x 20.5
Hallmark Swirl Candy Tree Small features wood designed red and green swirl candy circles of varying sizes to create a fun festive Christmas tree. 12" tall
Brand new!!
Brand new!!
Halloween Bowl w/ Speader comes in three different styles to choose from: Skeleton, Ghost, or Jack-O-Lantern. 6 x 6 x 3.75
Hallmark red and green peppermint swirl measuring spoons. Set includes three spoons including tblsp, tsp, and 1/2 tsp.
Hallmark Bunny Treat Dish features a white bunny holding a pale yellow nest. Made of ceramic and measures 6.75 x 4.95 x 4.5
Hallmark Tiny Talkers Sugar Buzzed Bunny will say funny phrases when you press the button.
Green Glitter Resin Tree features sparkly green resin Christmas tree figure covered in glitter and sequins, adorned with red holly berry and evergreen needles. Stands 12"
Hallmark Christmas Tree Magnetic Countdown Calendar comes with 25 magnets to count down days till Christmas.
Hallmark Flower Divided Serving Dish is made of a hard plastic and measures 13" x 13" x 1.5".
Halloween Ceramic Jack-O-Lantern Treat Bowl comes in black and white polka dots, purple polka dots, or orange and black stripes. 7 x 6 x 2
Halloween Welcome LED sign features a spooky haunted house scene with full moon and bats. Lights with LED lights. Requires 2 AA batteries (not included), 10" x 12"
Halloween If You Dare LED lit sign features cemetary silhouette. Requires 2 AA batteries. 17.75" x 6"
Hallmark Swirl Candy Tree Large features wood designed red and green swirl candy circles of varying sizes to create a fun festive Christmas tree. 18" tall
Hallmark Swirl Candy Tree Medium features wood designed red and green swirl candy circles of varying sizes to create a fun festive Christmas tree. 16" tall
Halloween Nylon Feather Flags with spring come in four different styles to choose from: Black Cat, Ghost, Jack-O-Lantern, or Skeleton. 0.25 x 16 x 45
Brand New! Ships within 1 business day!
Hallmark Large and Small Stacking Mugs Set of 2 comes with two mugs, one reading "Big Sipper" the other "Little Dripper." Comes as gift set tied with red ribbon. Made of ceramic
Hallmark ceramic red edged platter with white center and the word "Joy" in middle. 12 x 7
Hallmark Blooming Expressions Princess Pink Bloom will open to reveal message "Be-YOU-tiful" when button is pushed. Vase says My Little Princess. 9" tall
Blooming Expressions Family Yellow Bloom will open to reveal message "You make everything beautiful." Vase reads "Family makes everything more beautiful." White flower with yellow tips. 9" tall
Brand New!!
Brand New!
Christmas Dish Towel Set includes three dish towels, one red, one green, and one white with red, white and green design with embroidered message. Comes in three different styles to choose from: Tis the Season, Let it Snow, or Merry Christmas.
Hallmark Love Ya Pup Plush features sound and motion. Press the button and pup will flap his ears and say "Who do I love? You-ooooooohhh!"
Hallmark Hoppy Spring Bunny Plush is a super soft stuffed rabbit with floppy ears and big feet. 6" x 11" x 7"
Hallmark Pink Plush Bunny Rabbit features super soft pink plush fur with pink ribbon tied around neck.
Hallmark Plush Bunny Rabbit features super soft tancolored plush fur with green ribbon tied around neck.
Rustic Pine Cone Resin Snowman features snowman atop wood look base with intertwined white washed glitter deco ball look body, stick arms holding nest in one hand and metal string spelling out Noel in other. Snowman is topped off with pine cone hat and features red berry embellishments throughout as well as evergreen needle and pine cone "buttons." Snowman base lights up. Requires 3 AA batteries. Batteries not included. Stands 19" tall
Resin Choir Family w/LED light features family of four on snow covered base, caroling in front of street lamp. Street lamp lights when button is pushed. Figure stands 16"
Rustic Pine Cone Resin Snowman features snowman atop wood look base with intertwined white washed glitter deco ball look body, stick arms holding cardianl in one hand and metal string spelling out Joy in other. Snowman is topped off with pine cone hat and features red berry embellishments throughout as well as evergreen needle and pine cone "buttons." Snowman base lights up. Requires 3 AA batteries. Batteries not included. Stands 15" tall
Large Spider on Web comes in black or purple. 1 x 20.5 x 20.5
Resin Wood Look Light Up Snowman features faux wood carved look snowman with hollowed out center featuring light up house. Snowman stands 13" H
AM PM Kids Infant Toddler Owl Costume includes owl body with wings that attach to arms and owl head hood that ties. Fits infants and toddlers up to 35 pounds. Polyester satin.
Brand New!! Ships within 1 business day!
Brand New!!!
Metal Halloween Candelabra features scrolled pedestal with spiderweb design on top. Holds five tea light candles. Comes in black or orange.
Fur Trimmed Silver and White Snowflake Replica Ice Skates features silver resin blades topped with white skates adorned with silver glitter snowflakes and silver laces. Skates are topped with white fur trim. 12" x 11"
Metal Witch Boots Figure reads "If the Shoe Fits..." with decorative black witch boots with purple and orange accents. 2 x 15.5 x 17
Metal Halloween Owl Figure comes in two varieties to choose from: Jack-O-Lantern or Trick or Treat. 3.25 x 12.25 x 22.5
Hallmark Halloween Shadows and Shrieks Framed Print features a motion activated haunted house that lights up and plays spooky sounds. Includes 3 AAA batteries. Easel on back or can be hung.
LED Top Hat Snowman features white and silver glittered snowman with red and white striped scarf, stick arms, and tall top hat. Snowman lights when battery pack is turned on. 8.5" x 15.25" x 21"
Nativity features manger with Mary, Joseph, angel, baby Jesus, and animals. Nativity is silver with gold accents and mirrored jewels throughout. 10"' x 11" x 4"
Brand New in Box!!
Hallmark Santas From Around the World England Tabletop features ornate porcelain body with intricate detail. 12" tall
Resin Light Up Birdhouse on Stand features red birdhouse upon tree trunk base decorated for holidays with holly berry and greenery adorned with red bow. Top of birdhouse lights when button is pushed.
Brand New in box in plastic!
Resin Nativity Set features 11 piece large figure set including three wise men, angel, Mary, Joseph, baby Jesus and animals. Largest figure stands 12" tall
Resin Holy Family features large figures of Joseph, Mary and baby Jesus. Largest figure stands 36" tall.


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'Pretty Little Liars' Cast On 'The View' Video 2016: Watch 'PLL' Winter Premiere Interview Here!
The cast of "Pretty Little Liars" sat down for an interview on "The View" on Tuesday to discuss the winter premiere, which will air Tuesday night on Freeform. Watch below!
The chat began with Raven-Symone expressing incredulity that it took six and a half seasons to find out who Big A was. That occurred on the summer finale last August, and now the midseason premiere will pick up five years later with a new Uber A. Shay Mitchell (Emily) noted, "Our show has been a mystery ever since we started, and there's so many surprises that the fans get to watch."
As for the time jump, Troian Bellisario (Spencer) offered, "I think it's going to be really fun for our fans. When you first saw the show, you got to meet these girls, you got to find out over the course of the six seasons a lot about their lives, and now that five years have passed, it's like they have whole new lives, whole new secrets."
Ashley Benson (Hanna) was revealed to be the on-set prankster, and everyone marveled at how Sasha Pieterse (Alison) was only 12 when she started filming the pilot. "This has been such an amazing experience, and I think I can speak for everyone when I say this is a chapter of our lives that we will definitely cherish," she told Candace Cameron Bure.
As Gossip Cop reported, the cast started the day on "GMA," and Hale went on to do "Live With Kelly And Michael," where she willingly ate bugs. Check out full video from "The View" below! NOTE: The video is no longer available.


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Results 1 to 5 of 5
Thread: Report misbehaving
11-29-04, 05:31 #1Registered User
- Join Date
- Sep 2004
- Location
- Raleigh, NC
- Posts
- 146
Unanswered: Report misbehaving
I have a report that contains a calculated subtotal in the detail section. In the footer section, I'm trying to SUM up all of the subtotals. I'm aware that you can't SUM from the footer section, so I created a textbox in the detail section that SUMs the subtotals and then I simply used that box as the control source for my grand total in the footer. The problem is, when I run the report, I'm asked for a Parameter Value for the total control in the footer. For some reason, it's not behaving. Does anyone have any ideas?
11-29-04, 06:14 #2Jaded Developer
Provided Answers: 59
- Join Date
- Nov 2004
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- out on a limb
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- 13,692
As far as I'm aware you can use sum in the footers, if you copy the same formulas access handles the grouping fine. Failing that I have also done code controlled aggregations.
<basic method is>
declare the variables to be before the first sub or function in your form
insert some code to zero the variables on change of the groupings, in the group header format event
in the detail format event add your code to calculate the sum
create control(s) to act as placeholder(s) for the fields to be summed / aggregated in the group footer
in the group footer format event transfer the summed varaiable(s) to the placeholder(s)
you can do the same in the page & report footer format events aswell
11-29-04, 17:08 #3Purveyor of Discontent
Provided Answers: 1
- Join Date
- Mar 2003
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- The Bottom of The Barrel
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- 6,102
Is there a reason you're not using the report footer?oh yeah... documentation... I have heard of that.
*** What Do You Want In The MS Access Forum? ***
11-29-04, 18:24 #4Registered User
- Join Date
- Sep 2004
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- Raleigh, NC
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- 146
I was printing grouped reports and needed the total to remain with the group. I used a running sum (over group) in the detail section, hid duplicates, and then passed the value of that control to a textbox in the group footer. Might not be elegant, but it worked just fine.
11-29-04, 19:42 #5Registered User
- Join Date
- Nov 2004
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- 32
asking for parameter value
Any time that you get asked for a parameter value and you are not expecting it. It is because Access can not find the object that was refrenced usually indicating a typo in your formula. So possibly you are over compilcating the problem and it is just a typo or mis-spelling.