A systematic review of care delivery models and economic analyses in lymphedema: health policy impact (2004-2011).

A project of the American Lymphedema Framework Project (ALFP), this review seeks to examine the policy and economic impact of caring for patients with lymphedema, a common side effect of cancer treatment. This review is the first of its kind undertaken to investigate, coordinate, and streamline lymphedema policy initiatives in the United States with potential applicability worldwide. As part of a large scale literature review aiming to systematically evaluate the level of evidence of contemporary peer-reviewed lymphedema literature (2004 to 2011), publications on care delivery models, health policy, and economic impact were retrieved, summarized, and evaluated by a team of investigators and clinical experts. The review substantiates lymphedema education models and clinical models implemented at the community, health care provider, and individual level that improve delivery of care. The review exposes the lack of economic analysis related to lymphedema. Despite a dearth of evidence, efforts towards policy initiatives at the federal and state level are underway. These initiatives and the evidence to support them are examined and recommendations for translating these findings into clinical practice are made. Medical and community-based disease management interventions, taking on a public approach, are effective delivery models for lymphedema care and demonstrate great potential to improve cancer survivorship care. Efforts to create policy at the federal, state, and local level should target implementation of these models. More research is needed to identify costs associated with the treatment of lymphedema and to model the cost outlays and potential cost savings associated with comprehensive management of chronic lymphedema.

Intermittent pneumatic compression therapy: a systematic review.

Intermittent pneumatic compression (IPC) therapy is an effective modality to reduce the volume of the lymphedematous limbs alone or in conjunction with other modalities of therapy such as decongestive therapy. However, there is no consensus on the frequency or treatment parameters for IPC devices. We undertook a systematic review of contemporary peer-reviewed literature (2004-2011) to evaluate the evidence for use of IPC in the treatment of lymphedema. In select patients, IPC use may provide an acceptable home-based treatment modality in addition to wearing compression garments.

Segmental blood flow and hemodynamic state of lymphedematous and nonlymphedematous arms.

BACKGROUND: Findings regarding the influence hemodynamic factors, such as increased arterial blood flow or venous abnormalities, on breast cancer treatment-related lymphedema are mixed. The purpose of this study was to compare segmental arterial blood flow, venous blood return, and blood volumes between breast cancer survivors with treatment-related lymphedema and healthy normal individuals without lymphedema. METHODS AND RESULTS: A Tetrapolar High Resolution Impedance Monitor and Cardiotachometer were used to compare segmental arterial blood flow, venous blood return, and blood volumes between breast cancer survivors with treatment-related lymphedema and healthy normal volunteers. Average arterial blood flow in lymphedema-affected arms was higher than that in arms of healthy normal volunteers or in contralateral nonlymphedema affected arms. Time of venous outflow period of blood flow pulse was lower in lymphedema-affected arms than in healthy normal or lymphedema nonaffected arms. Amplitude of the venous component of blood flow pulse signal was lower in lymphedema-affected arms than in healthy or lymphedema nonaffected arms. Index of venular tone was also lower in lymphedema-affected arms than healthy or lymphedema nonaffected arms. CONCLUSIONS: Both arterial and venous components may be altered in the lymphedema-affected arms when compared to healthy normal arms and contralateral arms in the breast cancer survivors.

Post-breast cancer lymphedema: incidence increases from 12 to 30 to 60 months.

Breast cancer survivors are at life-time risk of developing lymphedema (LE). Quantification of LE has been problematic as the criteria used to identify lymphedema use various methods to assess changes in the volume of the affected limb. In part because of difficulties and variability in measurement and diagnosis, the reported incidence of LE varies greatly among women treated with surgery and radiation for breast cancer. The goal of this research was to describe the trends for LE occurrence over three points in time (12, 30, and 60 months) among breast cancer survivors using four diagnostic criteria based on three measurement techniques. Participants were enrolled following diagnosis of breast cancer but before surgery. Baseline limb volume and symptom assessment data were obtained. Participants were followed every 3 months for 12 months, then every 6 months thereafter for a total of 60 months. Limb volume changes (LVC) in both limbs were measured using three techniques: objectively by (a) circumferences at 4 cm intervals and (b) perometry and subjectively by (c) symptom experience via interview. Four diagnostic criteria for LE most often reported in the literature were used: (i) 2 cm circumferential change; (ii) 200 mL perometry LVC; (iii) 10% perometry LVC; and (iv) signs and symptoms (SS) report of limb heaviness and swelling, either 'now' or 'in the past year' (diagnostic criteria i-iii define increases/differences in limb volume from baseline and/or between the affected and non-affected limb). Standard survival analysis methods were applied to identify when the criteria corresponding to LE were met. Trends in LE occurrence are reported for preliminary analysis of data from 236 participants collected at 6-, 12-, 18-, 24-, 30-, and 60-months post-op. At 60 months post-treatment, LE incidence using the four criteria ranged from 43% to 94%, with 2 cm associated with the highest frequency for lymphedema occurrence and SS the lowest. Sixty-month trends are compared to earlier trends at 12- and 30-months, per criterion. These preliminary findings provide additional evidence that breast cancer survivors are at risk for developing LE beyond the first year following treatment. Cases of lymphedema continue to emerge through 60-months post-breast cancer surgery. This 60-month analysis supports the previous 12- and 30-month analyses in finding the 2 cm criteria to be the most liberal definition of LE. The self-report of heaviness and swelling, along with 10% LVC, represent the most conservative definitions (41% and 45%, respectively). Furthermore, the variety of criteria used to identify LE, along with the absence of baseline (pre-treatment) measurements, likely contribute to the wide range of LE incidence rates reported in the literature.

Minimal limb volume change has a significant impact on breast cancer survivors.

We sought to define the incidence, risk factors, symptoms, and quality of life (QOL) outcomes associated with various degrees of postoperative limb volume change (LVC). A prospective cohort study was performed obtaining serial limb volume measurements using a perometer on 269 women undergoing surgery for breast cancer. Four groups were created based on maximum LVC: none < 5.0%, mild 5.0-9.9%, moderate 10.0-14.9%, and severe 15.0%. Symptoms and QOL were assessed. 81 (30.1%), 70 (26.0%), and 14 (5.2%) women developed mild, moderate, and severe LVC, respectively. Increases in body mass index (p < 0.001) and post-operative complications (p = 0.002) were associated with increasing LVC. Lower QOL scores were associated with a moderate LVC (OR = 3.72, 95% CI, 1.29-10.73, p = 0.015) and postoperative infections (OR = 5.04, 95% CI, 1.73-14.70, p = 0.003). LVC at 5.0% occurs in up to 61.3% of breast cancer survivors and is associated with a significant increase in symptoms and a change in reported quality of life.

Comparison of upper limb volume measurement techniques and arm symptoms between healthy volunteers and individuals with known lymphedema.

Lymphedema is a problem for breast cancer survivors. The proliferation of limb measurement techniques makes it difficult to know how best to measure an at-risk limb. Using a sample of healthy volunteers and individuals with lymphedema, this study: 1) examined the relationship between more commonly used circumferential limb measurement methods and newer measurement methods of infrared laser perometry and bioelectrical impedance; 2) compared self-reported arm symptoms in healthy volunteers and breast cancer survivors with known lymphedema; and 3) explored the relationships among self-reported arm symptoms and circumferential tape measurement, infrared laser (perometry), and single and multi-frequency bioelectrical impedance. Lymphedema index ratios were calculated to allow comparison among measurement methods. Measurement methods correlated strongly with each other. Fourteen symptoms were reported by one or more participants in the lymphedema group while participants in the healthy volunteer group reported only eight symptoms over the same time frames. Using p < 0.001, all measurement methods correlated with self-reported arm swelling in the past year, while only circumferential and impedance measurements correlated with firmness. Future research needs to include serial arm measurements to explore arm volume variation in healthy and lymphedema volunteers and to further investigate possible lymphedema index ratios cut points as lymphedema diagnostic criteria.

Evaluation of leachates from coal refuse blended with fly ash at different rates.

There is great interest in returning coal combustion products to mining sites for beneficial reuse as liming agents. A column study examined the effects of blending two coal fly ashes with an acid-forming coal refuse (4% pyritic S). Both fly ashes were net alkaline, but had relatively low neutralizing capacities. One ash with moderate alkalinity (CRF) was bulk blended with coal refuse at 0, 20, and 33% (w/w), while another lower alkalinity ash (WVF) was blended at 0, 5, 10, 20, and 33% (w/w). The columns were leached (unsaturated) weekly with 2.5 cm of simulated precipitation for >150 wk. Where high amounts of ash alkalinity (>20% w/w) were mixed with the coal refuse, pyrite oxidation was controlled and leachate pH was >7.0 with low metal levels throughout the study. At lower rates of alkalinity loading, trace metals were sequentially released from the WVF ash as the 5, 10, and 20% treatments acidified due to pyrite oxidation. Lechate metals increased in proportion to the total amounts applied in the ash. In this strongly acidic environment, metals such as Mn, Fe, and Cu were dissolved and leached from the ash matrix in large quantities. If ash is to be beneficially reused in the reclamation of acid-producing coal refuse, the alkalinity and potential acidity of the materials must be balanced through the appropriate addition of lime or other alkaline materials to the blend. Highly potentially acidic refuse material, such as that used here, may not be suitable for ash/refuse codisposal scenarios.

Fractalkine cleavage from neuronal membranes represents an acute event in the inflammatory response to excitotoxic brain damage.

Fractalkine is a recently identified chemokine that exhibits cell adhesion and chemoattractive properties. It represents a unique member of the chemokine superfamily because it is located predominantly in the brain in which it is expressed constitutively on specific subsets of neurons. To elucidate the possible role of neuronally expressed fractalkine in the inflammatory response to neuronal injury, we have analyzed the regulation of fractalkine mRNA expression and protein cleavage under conditions of neurotoxicity. We observed that mRNA encoding fractalkine is unaffected by experimental ischemic stroke (permanent middle cerebral artery occlusion) in the rat. Similarly, in vitro, levels of fractalkine mRNA were unaffected by ensuing excitotoxicity. However, when analyzed at the protein level, we found that fractalkine is rapidly cleaved from cultured neurons in response to an excitotoxic stimulus. More specifically, fractalkine cleavage preceded actual neuronal death by 2-3 hr, and, when evaluated functionally, fractalkine represented the principal chemokine released from the neurons into the culture medium upon an excitotoxic stimulus to promote chemotaxis of primary microglial and monocytic cells. We further demonstrate that cleavage of neuron-derived, chemoattractive fractalkine can be prevented by inhibition of matrix metalloproteases. These data strongly suggest that dynamic proteolytic cleavage of fractalkine from neuronal membranes in response to a neurotoxic insult, and subsequent chemoattraction of reactive immune cells, may represent an early event in the inflammatory response to neuronal injury.

The role of fractalkine in the recruitment of monocytes to the endothelium.

Recombinant fractalkine possesses both chemoattractive and adhesive properties in vitro. Previous studies have demonstrated an upregulation of this molecule on the membranes of activated human endothelial cells and hypothesised that fractalkine plays a role in the recruitment and adherence of monocytes to the activated endothelium. Here we present data analysing both the adhesive and chemoattractive properties of this chemokine expressed by activated human umbilical vein endothelial cells. We demonstrate that both recombinant fractalkine and endogenously produced fractalkine function as adhesion molecules, tethering monocytes to the endothelium. However, our data demonstrate that although recombinant fractalkine has the potential to function as a potent monocyte chemoattractant, the endogenous fractalkine cleaved from activated human umbilical vein endothelial cells is not responsible for the observed chemotaxis in this model. Instead, we show that monocyte chemoattractant protein-1 (MCP-1), secreted from the activated human umbilical vein endothelial cells, is responsible for the chemotaxis of these monocytes.

Antitrust implications of alternative delivery systems.

Collaborative arrangements between clinical labs have created new opportunities for market development and the efficient delivery and production of services. As with any joint effort between otherwise competing entities, however, these arrangements are subject to federal and, some cases, state antitrust laws designed to ensure that the market performs in the most efficient way possible, a result believed best achieved through the preservation of competition. As a result, both the formation and operation of the new arrangement will be analyzed to ensure that its anticompetitive effects, if any, are minimal and are outweighed by the arrangement's procompetitive efficiencies. At the formation stage, the new entity will be analyzed to determine whether the participants would be able to exercise market power, which, in antitrust jargon, means the ability to raise prices above the competitive level. At the operational stage, the new entity will be analyzed to determine whether agreements among participants, primarily agreements on price, are necessary for the efficient operation of the new enterprise. This article addresses these basic antitrust principles.

Induction of purposeless chewing behaviour in rats by 5-HT agonist drugs.

The 5-HT agonist m-chlorophenylpiperazine (m-CPP; 1-16 mg/kg i.p. or s.c.), trifluoromethylphenylpiperazine (TFMPP; 2-16 mg/kg i.p.) and quipazine (2.5-20 mg/kg i.p.) increased purposeless chewing behaviour in rats. However, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.025-4 mg/kg s.c.) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT; 0.25-8 mg/kg s.c.) were without effect on chewing behaviour. Chewing behaviour induced by m-CPP (6 mg/kg s.c.) was antagonised by pretreatment with the 5-HT antagonists methiothepin and mianserin, but not by ketanserin or spiperone, or ICS 205-930. m-CPP (6 mg/kg s.c.)-induced chewing behaviour was also antagonised by pretreatment with (-)-propranolol (20 mg/kg). Pretreatment with the anticholinergic drugs benzhexol (2.5 mg/kg), and scopolamine (1 mg/kg) antagonised m-CPP (6 mg/kg s.c.)-induced chewing behaviour, but methylscopolamine (1 mg/kg) had no effect. These data support the role of 5-HT receptors in the mediation of purposeless chewing behaviour and suggest an interaction between brain 5-HT and acetylcholine systems.

Assessment of the muscarinic receptor subtype involved in the mediation of pilocarpine-induced purposeless chewing behaviour.

Purposeless chewing behaviour in rats was enhanced by intraperitoneal administration of the muscarinic agonists pilocarpine (1.0-8.0 mg/kg), RS 86 (0.5-0.8 mg/kg), oxotremorine (1-2 mg/kg) and arecoline (2-32 mg/kg), but not by nicotine (0.1-3.2 mg/kg). Chewing behaviour was also induced by the ICV administration of the muscarinic agonists carbachol (12.5-100 micrograms) and pilocarpine (50-200 micrograms), but not by the putative M-1 receptor agonist McN-A-343 (50-200 micrograms) or AH 6405 (100-200 micrograms). The muscarinic receptor antagonists scopolamine (0.01-0.1 mg/kg SC), benzhexol (0.075-2.5 mg/kg SC), secoverine (1-10 mg/kg SC), and dicyclomine (1.25-10 mg/kg SC) antagonised purposeless chewing behaviour induced by pilocarpine (4 mg/kg IP). AF-DX 116 (2.5-100 mg/kg SC), an M-2 antagonist, partially inhibited the actions of pilocarpine (4 mg/kg IP). Based on ED40 values the rank order of potency following IP administration was scopolamine greater than benzhexol greater than secoverine greater than dicyclomine greater than AF-DX 116. The ICV administration of the muscarinic antagonists N-methylscopolamine (2.5-10 micrograms) and oxyphenonium (10-40 micrograms) antagonised chewing behaviour induced by pilocarpine (4 mg/kg IP) in a dose-related manner. The M-2 antagonist 4-DAMP (40-160 micrograms ICV), as well as AF-DX 116 (40-160 micrograms ICV), also inhibited the effects of pilocarpine (40-160 micrograms ICV). The putative M-1 receptor antagonist pirenzepine (80-320 micrograms ICV) did not antagonise chewing behaviour induced by pilocarpine (4 mg/kg IP).(ABSTRACT TRUNCATED AT 250 WORDS)

Apomorphine-induced limb flicks in cats: the role of dopamine receptors located outside the blood-brain barrier.

Apomorphine-induced limb flicks in cats have been ascribed to a central dopamino-mimetic action of the drug. In these experiments we investigated the role of receptors located outside the blood-brain barrier (BBB) in the induction of limb flicking. Domperidone, a dopamine-receptor blocker which does not readily pass through the BBB, antagonised the induction of limb-flicks induced by apomorphine. This suggests that limb flicking behaviour may involve interactions with receptors located before the BBB. In contrast, 6-amino-5,6,7,8-tetrahydro-1,2-naphtalenediol HBr (6-ATN), a dopamine-agonist which does not penetrate the BBB, did not induce limb flicks, indicating that receptor stimulation outside the BBB alone is not sufficient to induce limb flicks. We suggest that limb flicks in cats is a behaviour which can be elicited by combined activation of centrally located dopamine receptors and dopamine receptors in the area postrema.

The pharmacological characterisation of pilocarpine-induced purposeless chewing behaviour in the rat.

Purposeless chewing in rats was induced by the acute administration of the cholinergic agonist pilocarpine or by physostigmine. Pilocarpine-induced chewing was antagonised by the centrally acting anticholinergic drugs scopolamine, benzhexol and secoverine, but not by the peripherally acting anticholinergic drug methylscopolamine. Both benzhexol and secoverine caused dose-dependent inhibition of pilocarpine-induced chewing. The D-2 antagonist sulpiride and the D-1 antagonist SCH 23390 did not inhibit pilocarpine-induced chewing. The non-selective neuroleptics pimozide, trifluoperazine and thioridazine also were inactive. In contrast, clozapine caused a dose-related inhibition of pilocarpine-induced chewing. The alpha-1 antagonist prazosin, the alpha-2 antagonist idazoxan, the beta-antagonists propranolol and metoprolol and the H-1 antagonist mepyramine did not reduce pilocarpine-induced chewing. Purposeless chewing behaviour induced by pilocarpine was reduced in a dose-related manner by the administration of the 5-HT antagonists methiothepin and mianserin, but not by spiperone or ketanserin. These data confirm that pilocarpine-induced chewing behaviour in the rat is a model of central cholinergic activity, but suggest that a serotonergic component may be involved in the mediation of this behaviour.

Effect of mu and kappa opioid receptor agonists on rat plasma corticosterone levels.

The effect of several mu and kappa opioid receptor agonists on rat plasma corticosterone levels, measured using radioimmunoassay, was investigated. The mu agonists, morphine and fentanyl, and the kappa agonists, U-50,488, tifluadom and bremazocine, all produced dose-related increases in rat plasma corticosterone levels. The effects of both fentanyl and U-50,488 were reversed by naloxone, indicating an action at opioid receptors. Pretreatment of the rats with the irreversible, mu-selective antagonist, beta-funaltrexamine, reduced the effect of fentanyl, but not that of U-50,488, indicating that both mu and kappa opioid receptors are involved in mediating this effect.

Regulation of gene activity by dosage compensation at the chromosomal level in drosophila.

Two models of dosage compensation have been tested by the measurement of G6PD and 6PGD enzymatic specific activities in flies hyperploid for regions of the X chromosome. Females duplicated for the proximal half of the X chromosomes (2 1/2 X's) have an increased level of G6PD and a normal level of 6PGD. Females duplicated for the distal half of the X chromosome (2 1/2 X's) have a normal level of G6PD and an increased level of 6PGD. Males bearing duplications of various segments of the X chromosome show control levels of G6PD and 6PGD, except where the duplicated region includes the structural gene for G6PD or 6PGD. These results fail to provide evidence for either the presence of discrete X-linked compensator (regulator) genes reducing the activity of other X-linked genes, or for a factor in limiting supply necessary for the transcription of all the genes on the X chromosome. Superfemales (3 X chromosomes) have the same G6PD and 6PGD activity levels as their diploid sisters. It would appear that the regulation of gene activity by dosage compensation is a chromosomal phenomenon in that the level of activity per gene copy for loci on the X chromosome is modulated in a stepwise fashion according to the total number of X chromosomes present.

Segmental aneuploidy and enzyme activity as a method for cytogenetic localization in drosophila melanogaster.

A method of mapping genes which specify enzymes without the necessity of obtaining genetic variants has been explored. Three enzymes whose structural genes have known genetic positions were chosen to see if the relationship between gene dosage and enzyme activity could be used as a tool in cytological localization. Zw, the gene specifying G6PD, is located in the X chromosome region, 18D-18F. The structural gene for 6PGD, Pgd, maps in the X chromosome bands 2C1-2E1. Idh-NADP, the gene which specifies IDH-NADP, is found on the third chromosome, in bands 66B-67C.