Changing roles of eosinophils in health and disease.

OBJECTIVE: To review and highlight the unappreciated roles of eosinophils suggested by recent studies. DATA SOURCES: The literature, unpublished observations, and insights by the authors. STUDY SELECTIONS: Basic studies of mouse models and patient-based clinical studies of disease. RESULTS: Eosinophils are often thought of as destructive end-stage effector cells primarily linked to parasite host defense and dysregulated immune responses associated with allergic diseases, such as asthma. However, recent studies (ie, research focused on mechanisms of action and translational studies examining disease/inflammatory pathways) are suggesting far more complex roles for eosinophils. The goal of this review is 3-fold. (1) The authors examine the dynamic history of eosinophils and how physicians over time used this information to formulate defining hypotheses. Particular emphasis is placed on recent studies challenging the parochial view of host defense in favor of roles maintaining homeostasis through immune modulation and tissue remodeling/repair. (2) They discuss diagnostic approaches to assess eosinophils in clinical settings as a means of disease identification and subsequently as a measurement of disease severity. (3) They examine how contemporary views of eosinophils and their perceived roles in diseases have led to specific therapeutic strategies. The emphasis is to review the successes and failures of these strategies as the basis of formulating future clinical studies targeting eosinophils as potential therapies of disease. CONCLUSION: Despite the complexities of eosinophil-mediated activities and the less than overwhelming success of initial attempts targeting these cells, eosinophils remain a potentially important focal target of disease diagnosis and subsequent treatment strategies.

The relative frequency in which empiric dosages of radioiodine would potentially overtreat or undertreat patients who have metastatic well-differentiated thyroid cancer.

The dosage of (131)I for the treatment of metastatic well-differentiated thyroid cancer is typically selected empirically. Benua and Leeper implemented a method to estimate the maximum dosages of (131)I that could be administered to a patient so as not to exceed a maximum tolerated radiation absorbed dose (MTD), which was defined as 200 rads (cGy) to the blood. The objective of this study was to determine the frequency of (131)I treatments in which the patient (1) would have exceeded the MTD (i.e., overtreatment) or (2) would have been able to receive higher dosages of (131)I thereby delivering a potentially higher radiation absorbed dose to their metastases (i.e., undertreatment) had the patient been administered various assumed empiric dosages of (131)I. The dosimetrically-determined maximum tolerated radioactivities (MTA) to deliver 200 rads to the blood (MTD) were tabulated at our facility. Data were then grouped to determine the percentage of patients who would have received less than or more than the MTD for various assumed empiric dosages of (131)I. A total of 127 dosimetries were performed. For assumed empiric dosages of (131)I (100 mCi, 150 mCi, 200 mCi, 250 mCi, and 300 mCi), the percentage of treatments for which patients would have exceeded the MTD were less than 1%, 5%, 11%, 17%, and 22%, respectively, and could have received a higher dosage of (131)I were more than 99%, 95%, 89%, 83%, and 78%, respectively. A significant number of patients receiving various empiric dosages of (131)I may exceed 200 rads (cGy) to the blood (potential overtreating). Likewise, the majority of patients may be able to receive much higher dosages of (131)I relative to empiric dosages thereby delivering potentially higher radiation absorbed doses to the metastases without exceeding 200 rads (cGy) to the blood (potential undertreating).

Reduction of brown fat 2-deoxy-2-[F-18]fluoro-D-glucose uptake by controlling environmental temperature prior to positron emission tomography scan.

UNLABELLED: Brown fat uptake of 2-deoxy-2-[F-18]fluoro-D: -glucose (FDG) on a positron emission tomography (PET) scan limits the ability to assess for cancer. Drugs such as benzodiazepine, propranolol, and reserpine have been proposed to reduce this uptake, but the studies have been either small clinical or preclinical trials. As an alternative, we evaluated the effect of controlling the patient's environmental temperature on brown fat uptake of FDG. METHOD: From January 1, 2002 to November 30, 2004, patients were identified who had (1) a pattern of FDG uptake in the neck/paravertebral areas suggestive of brown fat, (2) a repeat FDG-PET scan after control of the patient's environmental temperature, and (3) no evidence of cancer in the neck/paravertebral areas by other diagnostic methods. For the follow-up PET scan, all patients wore warm clothing and avoided exposure to cold air during their transit to our facility. After arrival, patients were kept in a separate temperature-controlled room (at least 75 degrees F) for 15 minutes to two hours before FDG injection as well as during the uptake phase. Four physicians blindly and retrospectively assessed the FDG uptake in the neck and paravertebral regions on all initial and temperature-controlled PET scans by visually grading the radioactivity on a semiquantitative scale (0 = background, 1+ = background but liver). The changes in maximal SUVs were determined in the left and right neck region. Data were evaluated using a two-tail t-test. RESULTS: Ten patients met the above criteria. The median age was 32 years with a range of 11-58 years. In comparing the semiquantitative uptake and the SUVs of FDG in the neck and paravertebral areas on the initial PET scan to the temperature-controlled PET scan, the mean decrease and the standard deviation of the decrease demonstrated a statistically significant decrease in with P values range from <0.02 to <0.001. CONCLUSION: Controlling the patient's environmental temperature prior to the dosing and during the uptake phase can significantly reduce FDG uptake in brown fat in the neck and paravertebral areas. Further studies are warranted to determine the most effective protocol to control the patient's environmental temperature in order to minimize brown fat uptake.

A consensus protocol for the determination of the threshold doses for allergenic foods: how much is too much?

BACKGROUND: While the ingestion of small amounts of an offending food can elicit adverse reactions in individuals with IgE-mediated food allergies, little information is known regarding these threshold doses for specific allergenic foods. While low-dose challenge trials have been conducted on an appreciable number of allergic individuals, a variety of different clinical protocols were used making the estimation of the threshold dose very difficult. OBJECTIVE: A roundtable conference was convened to develop a consensus clinical protocol for low-dose challenge trials for the estimation of threshold doses for specific allergenic foods. METHODS: In May 2002, 20 clinical allergists and other interested parties were invited to participate in a roundtable conference to develop consensus of the key elements of a clinical protocol for low-dose challenge trials. RESULTS: A consensus protocol was developed. Patients with convincing histories of food allergies and supporting diagnostic evidence including past challenge trials or high CAP-RAST scores can be enrolled in low-dose challenge trials. Care must be taken with younger patients to assure that they have not outgrown their food allergy. An approach was developed for the medication status of patients entering such trials. Challenge materials must be standardized, for example, partially defatted peanut flour composed of equal amounts of the three major varieties of peanuts (Florunner, Virginia, Spanish). Challenge materials must be appropriately blinded with sensory evaluation used to confirm the adequacy of blinding. A double-blind, placebo-controlled design should be used for low-dose challenge trials. Low-dose challenge trials would begin at doses of 10 microg of the allergenic food and would continue with doses of 100 microg and 1 mg followed by specific higher doses up to 100 mg depending upon the expert judgement of the physician; even higher doses might be applied to assure that the patient is indeed reactive to the particular food. A 30-min time interval would be used between doses, and reactive doses would be expressed as both discrete and cumulative doses. The goal of each challenge would be to develop objective symptoms; trials should not be discontinued on the basis of subjective symptoms only. Statistically, a minimum of 29 patients would be enrolled in low-dose challenge trials for each allergenic food because 0 reactors out of 29 patients at a particular dose allow the conclusion that there is 95% certainty that 90% of allergic individuals will not react to that dose. CONCLUSION: A consensus protocol was developed. Using this protocol, it will be possible to estimate threshold doses for allergenic foods, the lowest amount that elicits mild, objective symptoms in highly sensitive individuals.

Phase I and pharmacokinetic study of the novel MDR1 and MRP1 inhibitor biricodar administered alone and in combination with doxorubicin.

PURPOSE: To evaluate the safety, tolerability, and pharmacokinetics of biricodar (VX-710), an inhibitor of P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP1), alone and with doxorubicin in patients with advanced malignancies. The effect of VX-710 on the tissue distribution of (99m)Tc-sestamibi, a P-gp and MRP1 substrate, was also evaluated. PATIENTS AND METHODS: Patients with solid malignancies refractory to standard therapy first received a 96-hour infusion of VX-710 alone at 20 to 160 mg/m(2)/h. After a 3-day washout, a second infusion of VX-710 was begun, on the second day of which doxorubicin 45 mg/m(2) was administered. Cycles were repeated every 21 to 28 days. (99m)Tc-sestamibi scans were performed before and during administration of VX-710 alone. RESULTS: Of the 28 patients who enrolled, 25 patients were eligible for analysis. No dose-limiting toxicity (DLT) was observed in the nine assessable patients who received 120 mg/m(2)/h or less. Among seven patients receiving VX-710 160 mg/m(2)/h, two DLTs were seen: reversible CNS toxicity and febrile neutropenia. All other adverse events were mild to moderate and reversible. Plasma concentrations of VX-710 in patients who received at 120 and 160 mg/m(2)/h were two- to fourfold higher than concentrations required to fully reverse drug resistance in vitro. VX-710 exhibited linear pharmacokinetics with a harmonic mean half-life of 1.1 hours. VX-710 enhanced hepatic uptake and retention of (99m)Tc-sestamibi in all patients. CONCLUSION: A 96-hour infusion of VX-710 at 120 mg/m(2)/h plus doxorubicin 45 mg/m(2) has acceptable toxicity in patients with refractory malignancies. The safety and pharmacokinetics of VX-710 plus doxorubicin warrant efficacy trials in malignancies expressing P-gp and/or MRP1.

Technetium-99m-sestamibi parathyroid scintigraphy: effect of P-glycoprotein, histology and tumor size on detectability.

UNLABELLED: The purpose of this study was to evaluate the effect of P-glycoprotein (P-gp) levels, predominant histology and tumor size on the detectability of parathyroid adenomas with 99mTc-sestamibi scans. Although previous studies have shown that positivity correlates with tumor size, false-negative studies have been reported with large tumors and true-positives reported with very small tumors. Recent investigations have reported rapid washout of sestamibi in malignant tumors because of high levels of P-gp, similar to that seen with multidrug chemotherapy resistance. Therefore, we postulated that this mechanism might account for false-negative studies in parathyroid tumors. Preliminary reports have suggested that the predominant histological subtype influences positivity on 99mTc-sestamibi parathyroid scans. METHODS: We studied 25 patients with surgically confirmed parathyroid adenomas with 99mTc-sestamibi parathyroid scans. The results of the imaging study were correlated with tissue P-gp levels, predominant histological subtype and size of the surgically removed glands. RESULTS: There were 21 true-positive and 4 false-negative results. The size of the adenomas ranged from 0.12 to 8.64 ml. We found no correlation between the results of the dual-phase 99mTc-sestamibi study and either the predominant cell type or the level of P-gp. Positivity did correlate with the size of the adenoma (p=0.73, p < 0.0001). We cannot exclude the possibility that P-gp and cell type may still play a role in individual cases, but we suspect that other yet to be determined factors may influence 99mTc-sestamibi detectability in addition to tumor size.

Lag phase quantification for solid gastric emptying studies.

UNLABELLED: This study compared the different calculation methods of the solid gastric emptying lag phase and evaluated the effect of the temporal sampling interval on the calculated value using the modified power exponential (MPE) method. METHODS: Twenty normal control subjects and 42 patients had anterior and posterior image acquisition on a multihead gamma camera, one frame per minute x 90. ROIs were selected for the stomach, gastric antrum and small bowel. Time-activity curves (TACs) were generated for anterior, posterior and geometric mean data. The lag phase was calculated using various methods such as transition point, starting index, first appearance of bowel activity (FABA), MPE and antral peak filling time. To determine the importance of the temporal sampling rate on the calculation of the lag phase by the MPE, intervals between 1 and 20 min were analyzed. RESULTS: The transition point, starting index and FABA correlated extremely high (r = > or = 0.92) in normal control subjects and patients. Normal lag phase values were mean 22-24 +/- 10 min for transition point, starting index and FABA compared with 47 +/- 18 min for the MPE method (p < 0.0001). The MPE correlated poorly with the other method (r = 0.74). Antral peak filling time correlated poorly (r = 0.47) with transition point, starting index and FABA, but somewhat better with the MPE (r = 0.70). Comparing 15-min versus 1-min sampling intervals using the MPE, 35% of subjects had values that differed by > or = 7.5 min and 10% had values differing by > or = 15 min. CONCLUSION: The lag phase calculated by the MPE correlated poorly with other methods, and its accuracy was limited by the rate of the temporal sampling. The transition point, starting index and FABA all highly correlated with each other; the latter is a particularly reliable physiological indicator and is easily quantified using a small-bowel TAC.

Frequency of extra-cardiac activity and its effect on 99Tcm-MIBI cardiac SPET interpretation.

There are limited published data concerning the frequency and relative intensity of abdominal activity on 99Tcm-methoxyisobutyl isonitrile (99Tcm-MIBI) myocardial perfusion scans and its effect on interpretation. We undertook a blinded prospective study to evaluate (1) the frequency and intensity of abdominal activity on single photon emission tomography (SPET) scans, (2) its effect on separate evaluation of rest and stress SPET images, and (3) its effect on clinical interpretation. Patients undergoing one-day rest-stress 99Tcm-MIBI scans were randomized to receive 99Tcm-MIBI obtained from one of two radiopharmacies. The rest plus exercise or rest plus intravenous dipyridamole scans of 303 patients were scored separately by three physicians for (1) intensity of abdominal activity and (2) its effect on scan evaluation. Nuclear reports generated independently of the blinded evaluation were reviewed to assess the effect of abdominal activity on clinical interpretation. There were no statistical differences between pharmacies. Abdominal activity was uncommon on the exercise but common on the rest and dipyridamole scans. The exercise scans differed from the rest and dipyridamole scans in the subgroups: intensity of abdominal activity equal to myocardium, and greater than myocardium (P < 0.001). There was no difference between the rest and dipyridamole scans. The effect on evaluation was moderate in 5% of the exercise, 46% of the dipyridamole and 37% of the rest scans, and severe in 1% of the exercise, 3% of the dipyridamole and 12% of the rest scans. Rest differed from exercise (P < 0.001) and from dipyridamole (P < 0.05). There was no difference between the dipyridamole and exercise scans. Based on the clinical reports, abdominal activity was a limitation to scan interpretation for 20 patients; in 5, the inferior wall could not be evaluated. Although abdominal activity was frequently observed on both the dipyridamole and rest scans, it was a limitation to clinical interpretation in a small fraction of the patients.

Positive technetium-99m-red blood cell gastrointestinal bleeding scan after barium small-bowel study.

A 53-yr-old man with hepatic insufficiency and portal hypertension was hospitalized and underwent a work-up for gastrointestinal bleeding requiring multiple transfusions. The initial evaluation included a negative upper and lower endoscopy and a barium exam of the small bowel. Both studies failed to demonstrate any pathology to explain the bleeding. Immediately following the barium study, the patient had active bleeding. Because of the significant amount of intestinal barium, angiography was deferred. Technetium-99m-red blood cell (RBC) scintigraphy was undertaken to identify the site of bleeding. Despite intestinal barium, the 99m-Tc-RBC scan demonstrated an active bleeding site in the small bowel in the left abdomen. Therefore, 99mTc-RBC scintigraphy can be of clinical utility for identification of gastrointestinal bleeding, despite the presence of intestinal barium.

Therapy dose calculation in Graves' disease using early I-123 uptake measurements.

A retrospective study was performed to assess the feasibility of using the 4-hour I-123 early uptake value in the calculation of the treatment dose of radioactive iodine in Graves' disease patients. The Graves' disease patients were randomly divided into two groups. Data from the first group of 35 patients were used to obtain a regression relationship between the early 4-hour uptake (EUp) and 24-hour late uptake values (LUp). This equation, LUp = -38.618 + 65.216 Log (EUp) was used to estimate the predicted late uptake (PUp) from (EUp) in the second group of 34 patients. LUp was used to calculate the I-131 therapy dose for treatment in these patients. In 28 clinically euthyroid patients, the 4-hour uptake I-123 radioactive iodine uptake (RAIU) ranged from 7% to 20% (mean, 12 +/- 3.5%). In 60 Graves' disease patients, the 4-hour RAIU ranged from 15% to 100% (mean, 57 +/- 24.8%). Of these, there were five patients with a normal 4-hour uptake, but elevated 24-hour uptake. LUp correlated well with PUp (r = 0.81162), as did the dose calculation based on predicted and observed 24-hour uptake values (r = 0.82204). Thus, same day measurement of uptake and treatment of Graves' disease is feasible.

Modulation of left and right ventricular beta-adrenergic receptors from spontaneously hypertensive rats with left ventricular hypertrophy and failure.

Inotropic responsiveness to beta-adrenergic stimulation is generally found to be depressed in cardiac hypertrophy and failure. To investigate whether inotropic responsiveness is associated with alterations in beta-adrenergic receptors in spontaneously hypertensive rats (SHR), we studied left ventricular myocardial contractile responses to isoproterenol and beta-adrenergic receptor density and affinity in age-matched rats (18 to 24 months), including SHR without heart failure, SHR with evidence of heart failure, and normotensive control Wistar-Kyoto rats (WKY). In the baseline state, papillary muscles from failing SHR demonstrated decreased isometric tension development and a reduction in maximal rate of tension development relative to normotensive WKY and compensated SHR. Compared with WKY, beta-adrenergic receptor density of the left ventricle was unchanged in nonfailing SHR and increased in failing SHR (P < .05 versus WKY and nonfailing SHR), and beta-adrenergic receptor affinity did not differ among groups. In the right ventricle, beta-adrenergic receptor density was decreased in failing SHR relative to WKY and nonfailing SHR, and beta-adrenergic receptor affinity was not different among groups. Muscle preparations did not exhibit a positive inotropic response to 10(-8) to 10(-5) mol/L isoproterenol or 6.3 mumol/L forskolin in either failing or nonfailing SHR, whereas a positive inotropic response to both drugs was observed in the normotensive WKY. The lusitropic response to isoproterenol and forskolin was intact and similar in both SHR groups and WKY. The findings suggest that in the SHR model of heart failure, impaired intrinsic left ventricular myocardial function and depressed inotropic responsiveness to beta-adrenergic stimulation are not associated with downregulation of the beta-adrenergic receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Beta-adrenergic receptors, adenylate cyclase activation, and myofibril enzyme activity in hypothyroid rats.

A previous study in intact animals assessed cardiovascular alterations in surgically thyroidectomized rats. Hemodynamic challenge via isoproterenol infusion identified abnormal left ventricular relaxation. Challenge by aortic occlusion revealed a latent deficiency in left ventricular contractility which was not apparent during beta-agonist challenge. The present study utilized left ventricular cardiac tissue obtained from the identical control and thyroidectomized animals from which intact heart hemodynamic information had been obtained. Biochemical systems were selected for evaluation based on demonstrated hemodynamic alterations, i.e., beta-adrenergic receptor number/function and contractile protein enzyme properties. The number of beta-receptors on hypothyroid cardiac membranes was significantly decreased, but receptor agonist affinity was not influenced. Basal adenylate cyclase activity in cardiac membranes from control and thyroidectomized rats was nearly identical; however, isoproterenol activation was diminished in hypothyroid cardiac membrane, particularly at the higher levels of beta-agonist stimulation. Adenylate cyclase enzyme activation by forskolin was not influenced by thyroidectomy; however, activation by sodium fluoride was reduced approximately 30% when compared with preparations from control rats. Cardiac myofibrillar enzyme activity for adenosinetriphosphatase (ATPase) was significantly lower in thyroidectomized rats. Despite reduced ATPase activity, myofibrillar calcium sensitivity was unaltered. Myofibrillar creatine kinase enzyme activity was not influenced by thyroidectomy; therefore, compartmentalized ATP regeneration potential via creatine kinase was enhanced relative to substrate utilization via ATPase. Thus hemodynamically significant cardiac influences of hypothyroidism are mediated, at least in part, via 1) reduced beta-receptor number, 2) diminished catecholamine-induced activation of adenylate cyclase, and 3) reduced myofibrillar ATPase activity.

Tumor activity confirmation and isodose curve display for patients receiving iodine-131-labeled 16.88 human monoclonal antibody.

A study was performed to correlate activity quantitation derived from external imaging with surgical tumor specimens in patients who received radiolabeled monoclonal antibody. Patients were given I-131 labeled 16.88 human antibody and scanned 3-5 times by planar and/or single photon emission computed tomography imaging methods to acquire time-dependent activity data in tumor and normal tissues. A method also was developed to assess the heterogeneous activity distributions in tumor samples. Postsurgical tumor and normal tissue samples were subdivided into volume elements (voxels) of 0.5 cm x 0.5 cm x 0.05 cm thick, which were used to verify the activity quantitation computed by the conjugate view method and to appraise the heterogeneity of radiolabeled antibody uptake. Through the use of the measured voxel activities, along with the time-dependent activity curves available for the entire tumor specimen derived from imaging, the cumulated activity and absorbed dose for each voxel were uniquely determined. The calculated total absorbed dose values were color-coded as isodose curves and overlaid on a correlated computed tomographic image. In two patients, activity quantitation derived from external imaging correlated with surgical tumor resection specimens within +/- 11%. The tumor-absorbed dose heterogeneity ratio was found to be as high as 10:1, with an average tumor to whole body absorbed dose ratio of 4:1. The mapping of activity with a histologic overlay showed a good correlation among activity uptake, the presence of tumor, and antigen expression on a microscopic scale. The resultant isodose curves overlaid on correlative computed tomographic scans represent the first images obtained with actual radiolabeled antibody biodistribution data in patients.

Stress and coping among Missouri rural and urban children.

A cross-sectional survey using a convenience sample of 157 Missouri rural and urban children (ages 8-13 years) yielded no significant differences in perceptions of stressors or use of coping strategies for dealing with those stressors between rural and urban children. The Feel Bad Scale and the Schoolagers' Coping Strategies Inventory measured the children's perceptions of stressors and use of coping strategies. Rural children experienced stressor levels equivalent to urban children, yet they were underserved in mental and physical health needs. The children studied reported self-care through coping strategies for management of their stressors. Longitudinal research is needed to identify the impact of stress and interventions on the health and behavior of children in rural settings.

Cardiovascular alterations in the hypothyroid rat.

We conducted the present studies in intact animals to assess alterations in integrated cardiovascular function due to hypothyroidism. Rats were surgically thyroidectomized or sham operated. Most obvious among the alterations detected under resting conditions was the bradycardia present in hypothyroid animals. Cardiac output was significantly reduced by slower heart rate; however, mean arterial blood pressure and left ventricular +dP/dt were maintained. Total peripheral resistance was increased in hypothyroid animals. Functional responsiveness to hemodynamic challenges unmasked additional characteristics. Thyroidectomized animals had normal stroke index-left ventricular end diastolic pressure relationships in response to rapid volume infusion. Peak left ventricular +dP/dt response to brief aortic occlusion was attenuated in thyroidectomized animals. Hypothyroid rats failed to augment left ventricular -dP/dt in response to isoproterenol challenge. Moreover, isoproterenol failed to reduce total peripheral resistance in the hypothyroid rat. Therefore, the hemodynamic responses observed in the intact, hypothyroid animal are consistent with the presence of (a) decreased cardiac contractile protein ATPase, (b) reduced calcium uptake by cardiac sarcoplasmic reticulum and (c) altered vascular adrenergic receptors. Many cellular and subcellular defects are compensated by integrative mechanisms operating under resting conditions, while other defects are unmasked only when examined in the intact, functional cardiovascular system undergoing hemodynamic challenge.

An uncertain future: children of mentally ill parents.

Research reports the uncertain outcome of variables affecting the life of a child of an MI parent. Nurses must avoid stereotyping children before assessment; they are to be in the forefront in assessing self-care skills and deficits to guide planning individual interventions for children and MI parents. Long-term research theory-based interventions will enhance mental health in high-risk children and families.

Children's perspective of stress and coping: an integrative review.

This integrative review of children's perceptions of stressors and coping strategies contained only 14 studies published from September 1979 to March 1989. Most of these descriptive studies were theory-based research using convenience samples of children (aged 8-12 years) in urban settings. Commonly identified stressful events were fear of negative evaluation (adult or peer), parental conflict or loss, and conflict with an adult. Categories of commonly identified coping strategies were social support, physical activities, and avoidance activities. Individual studies reported that more children tended to catastrophize than to cope; normal amounts of stress may enhance a familial tendency for migraines; increased information and age tended to increase the amount of active modes of coping while in the hospital; and children given frequent and complete information about their sibling's illness tended to be more positive about their own development. Recommendations for further research are included.