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PubMed2006

Interleukin-12-deficient mice are at greater risk of UV radiation-induced skin tumors and malignant transformation of papillomas to carcinomas.

Solar UV radiation-induced immunosuppression is a risk factor for nonmelanoma skin cancer. Interleukin (IL)-12 has been shown to possess antitumor activity and inhibit the immunosuppressive effects of UV radiation in mice. In this study, we generated IL-12 knockout (KO) mice on a C3H/HeN background to characterize the role of IL-12 in photocarcinogenesis. After exposure of the mice to UVB (180 mJ/cm2) radiation thrice a week for 35 weeks, the development of UV-induced tumors was more rapid and the tumor multiplicity and tumor size were significantly higher in IL-12 KO mice than their wild-type (WT) counterparts (P < 0.05-0.001). Moreover, the malignant transformation of UVB-induced papillomas to carcinomas was higher in IL-12 KO mice in terms of carcinoma incidence (55%, P < 0.001), carcinoma multiplicity (77%, P < 0.001), and carcinoma size (81%, P < 0.001). As IL-12 has the ability to repair UV-induced DNA damage, we determined this effect in our in vivo IL-12 KO mouse model. We found that UVB-induced DNA damage in the form of cyclobutane pyrimidine dimers was removed or repaired more rapidly in WT mice than IL-12 KO mice. Similarly, the UVB-induced sunburn cell formation is primarily a consequence of DNA damage. It was observed that UVB-induced sunburn cells were repaired rapidly in WT mice compared with IL-12 KO mice. The rapid removal or repair of UV-induced cyclobutane pyrimidine dimers or sunburn cells will result in reduced risk of photocarcinogenesis. Taken together, our data show that IL-12 deficiency is associated with the greater risk of photocarcinogenesis in mice, and this may be due to reduction in damaged DNA repair ability.

Animals↗
PubMed1987

The pulmonary vascular sequestration of neutrophils in endotoxemia is initiated by an effect of endotoxin on the neutrophil in the rabbit.

Endotoxemia causes neutrophil sequestration in the pulmonary vascular bed. Such sequestration may be a critical initiating event in the generation of microvascular injury, although the mechanisms that lead to this localization are not understood. To investigate these phenomena, the following study employed intravenous pulses of 111Indium-tropolonate-labeled neutrophils (111In-neutrophils), which circulated in the rabbit with normal kinetics and responded in a manner indistinguishable from unlabeled, circulating neutrophils in response to an intravenous injection of purified endotoxic lipopolysaccharide (LPS) or epinephrine. Pulmonary sequestration of 111In-neutrophils was assessed by quantitative external gamma camera scintigraphy of a lung suprahilar region of interest. Noninvasive assessment of radioactivity by this method accurately reflected total lung radioactivity, which was shown by autoradiography to be confined to the injected 111In-neutrophils. Intravenously administered LPS caused a marked, dose-dependent sequestration of 111In-neutrophils in the pulmonary vasculature, and exhaustive ultrastructural autoradiography showed discretely radiolabeled neutrophils located within pulmonary capillaries. A distinct effect was seen with an intravenous injection of as little as 100 ng per rabbit (i.e., 500 pg/ml blood). A 5-min ex vivo pretreatment of 111In-neutrophils with 10 ng to 10 micrograms/ml LPS in heat-inactivated plasma (which resulted in retention of as little as 500 pg LPS per 10(7) neutrophils) also caused dose-dependent pulmonary sequestration of the pretreated 111In-neutrophils but did not cause generalized neutropenia in recipient rabbits. There was no evidence of complement activation on the surface of pretreated neutrophils.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Effects of ROI definition and reconstruction method on quantitative outcome and applicability in a response monitoring trial.

PURPOSE: Quantitative measurement of tracer uptake in a tumour can be influenced by a number of factors, including the method of defining regions of interest (ROIs) and the reconstruction parameters used. The main purpose of this study was to determine the effects of different ROI methods on quantitative outcome, using two reconstruction methods and the standard uptake value (SUV) as a simple quantitative measure of FDG uptake. METHODS: Four commonly used methods of ROI definition (manual placement, fixed dimensions, threshold based and maximum pixel value) were used to calculate SUV (SUV([MAN]), SUV15 mm, SUV50, SUV75 and SUVmax, respectively) and to generate "metabolic" tumour volumes. Test-retest reproducibility of SUVs and of "metabolic" tumour volumes and the applicability of ROI methods during chemotherapy were assessed. In addition, SUVs calculated on ordered subsets expectation maximisation (OSEM) and filtered back-projection (FBP) images were compared. RESULTS: ROI definition had a direct effect on quantitative outcome. On average, SUV[MAN), SUV15 mm, SUV50 and SUV75, were respectively 48%, 27%, 34% and 15% lower than SUVmax when calculated on OSEM images. No statistically significant differences were found between SUVs calculated on OSEM and FBP reconstructed images. Highest reproducibility was found for SUV15 mm and SUV[MAN] (ICC 0.95 and 0.94, respectively) and for "metabolic" volumes measured with the manual and 50% threshold ROIs (ICC 0.99 for both). Manual, 75% threshold and maximum pixel ROIs could be used throughout therapy, regardless of changes in tumour uptake or geometry. SUVs showed the same trend in relative change in FDG uptake after chemotherapy, irrespective of the ROI method used. CONCLUSION: The method of ROI definition has a direct influence on quantitative outcome. In terms of simplicity, user-independence, reproducibility and general applicability the threshold-based and fixed dimension methods are the best ROI methods. Threshold methods are in addition relatively independent of changes in size and geometry, however, and may therefore be more suitable for response monitoring purposes.

Adult↗
PubMedDate not supplied

An optimal dual-size vial system for the cost-effective usage of Adenoscan.

BACKGROUND: Adenoscan (Fujisawa USA, Inc., Deerfield, Ill.) has been initially packaged in a 30 ml glass vial for single use only because it contains no preservative. This restricted usage has generated considerable waste and high cost for the patient. Although the new 20 ml vial of Adenoscan provides some reduction in waste, the savings offered by the 20 ml and 30 ml vial system is still not optimal. The purpose of this study was to investigate an optimal dual-size vial system that would provide limited amounts of waste while maintaining its practicality to satisfy different patient populations. MATERIALS AND RESULTS: The least waste for each potential combination (n = 344) of two vials was calculated by assuming that patient weights (30 to 200 kg) follow a normal distribution. The 6 ml and 15 ml vial combination had the least expected waste for lighter patient populations, and the 9 ml and 15 ml vial system had the least expected waste for heavier populations. The calculated wastes for 4207 patients (83 +/- 19 kg) undergoing adenosine stress myocardial perfusion studies at the Mayo Clinic were 10.5 +/- 9.3 ml (30 ml vial), 5.1 +/- 2.9 ml (20 ml and 30 ml vial system), 1.6 +/- 1.0 ml (6 ml and 15 ml vial system), and 1.8 +/- 1.2 ml (9 ml and 15 ml vial system). CONCLUSIONS: In general, both the 6 ml and 15 ml and 9 ml and 15 ml vial systems perform better than either the single 30 ml vial or the 20 ml and 30 ml vial system. Furthermore, the 6 ml and 15 ml vial combination offers the lowest expected waste for the actual patient population that underwent the adenosine stress myocardial perfusion imaging studies at our institution.

Cost-Benefit Analysis↗
PubMed1999

Clinical usefulness of scintigraphy with 99mTc-galactosyl-human serum albumin for prognosis of cirrhosis of the liver.

UNLABELLED: Scintigraphy with 99mTc-diethylenetriamine pentaacetic acid-galactosyl-human serum albumin (99mTc-GSA) is useful for evaluating hepatic functional reserve. We assessed the clinical usefulness of this technique, including its value in establishing a prognosis, in patients with cirrhosis of the liver. METHODS: Scintigraphy with 99mTc-GSA was performed in 10 healthy subjects, 42 patients with chronic hepatitis and 158 patients with cirrhosis. Computer acquisition of gamma camera data were started just before the injection of 99mTc-GSA. Time-activity curves for the heart and liver were generated from regions of interest (ROIs) for the heart and the entire liver. A receptor index was calculated by dividing the radioactivity of the liver ROI by that of the liver-plus-heart ROI 15 min after the injection. An index of blood clearance was calculated by dividing the radioactivity of the heart ROI at 15 min by that of the heart ROI at 3 min. RESULTS: The median receptor index was lower in patients with cirrhosis than in patients with chronic hepatitis or in healthy subjects, and the median index of blood clearance was higher. The receptor index was significantly lower when a complication (varices, ascites) was present. The index of blood clearance was significantly higher when a complication (varices and ascites) was present. Correlation of the two indices with classic indicators for functional reserve was significant. On the basis of the receptor index, the patients with cirrhosis were divided into two groups of roughly equal size: group A, receptor index over 0.85, and group B, receptor index 0.85 or less. On the basis of the index of blood clearance, the patients with cirrhosis were divided into two groups of roughly equal size: group A, index of blood clearance < 0.70, and group B, index of blood clearance > or = 0.70. The cumulative survival rates were lower in group B than in group A. CONCLUSION: Scintigraphy with 99mTc-GSA is clinically useful, especially in establishing the prognosis of patients with cirrhosis of the liver.

Ascites↗
PubMed1990

[Usefulness of a 201Tl dynamic study of thyroid tumors].

A thallium 201 dynamic study was performed on 39 patients with thyroid tumor by use of a digital gamma-camera, which was connected to the computer data system. They consisted of 12 patients with a benign lesion and 27 patients with a malignant lesion. Regions of interest (ROIs) were assigned for tumor, normal thyroid, and background. Time activity curves (TACs) were generated from these ROIs. The following six parameters were created from the TACs and compared between benign and malignant tumors: 1) Tmax, 2) T3/4max, 3) distribution index (DI) = peak count determined for a tumor divided by that for the normal thyroid, 4) mean transit time (MTT), 5) relative MTT (r-MTT) = MTT for a tumor divided by that for the normal thyroid, and 6) perfusion curve (PC) = TAC that is drawn on the basis of the quotients obtained by dividing A by B (A = counts in the individual frames determined for a tumor; B = those for the normal thyroid). Among the first five parameters, DI, T3/4max, and r-MTT were significantly different between the two sorts of lesions. To be more precise, DI was significantly lower (p less than 0.01) and T3/4max and r-MTT were higher (p less than 0.05) in the malignant group. PC was classified into three types: decreased type, parallel type, and increased type. In the benign group the PCs were decreased or parallel type in all cases except two. In the malignant group the PCs were parallel or increased type in all cases. In conclusion, the present observations suggest that thallium 201 accumulates in a malignant lesion at nearly the same rate as in the normal thyroid in an early phase, or otherwise its washout from the lesion is prolonged, and further that early-phase accumulation in a benign lesion is high and washout from the lesion is rapid compared with the normal thyroid. Functional images (peak count, MTT), which were obtained through computer analysis, facilitated visual diagnostic evaluation of thyroid tumor.

Adenocarcinoma↗
PubMed1982

Some chemical aspects of labeling human fibrinogen with 99m-technetium.

Human fibrinogen was labeled with 99m-Technetium. Tin(II)-chloride in citric acid served as reducing agent for the pertechnetate-ion, eluted from a Mo-Tc-generator. Before adding the fibrinogen, the citric acid was always neutralized with sodium hydrogen carbonate. The influences on the quantity of fibrinogen bound 99m-Tc of the relative concentrations of Sn(II), fibrinogen and sodium hydrogen carbonate, of the reaction time and temperature were tested by thin-layer chromatography. The reaction temperature of 28 degrees C showed an optimum of fibrinogen bound 99m-Tc for the reaction time from 1 and 2 hours. With a reaction time of 30 minutes not enough 99m-Tc was bound to fibrinogen, the doubling of the reaction time from 1 to 2 hours showed only an increase of binding of less than 4%. The concentration of Sn(II) with respect to the fibrinogen concentration showed no influence on the quantity of fibrinogen bound 99m-Tc at low Sn(II)-concentrations. At values higher than 34 times of the fibrinogen concentration a decrease of the quantity of bound 99m-Tc was observed. The concentrations of sodium hydrogen carbonate showed no influence on the quantity of fibrinogen bound 99m-Tc but on the clottability of fibrinogen, the pH of the solution must be approximately 7.5. In 3 parallel and independent experiments under optimized conditions (1 hour at 28 degrees C, molar ratio of Sn(II) : fibrinogen = 8.5, pH = 7.5) 89.97 +/- 0.92 % of 99 m-Tc were bound to fibrinogen. Controls of these results by column chromatography showed a binding of 81.08 +/- 1.47 % of 99m-Tc to fibrinogen. The clottability of fibrinogen tested by the method of Clauss (1) was entirely preserved.

Bicarbonates↗
PubMed2005

Positive expiratory pressure changes aerosol distribution in patients with cystic fibrosis.

HYPOTHESIS: We hypothesized that aerosol distribution in the lungs of patients with cystic fibrosis changes with positive expiratory pressure (PEP). METHODS: Eight patients were randomized to one of 2 conditions. On one study day, patients inhaled saline aerosol containing 99mtechnetium generated by a Pari LC Plus nebulizer and exhaled through a Pari PEP device. On another day, the same patients exhaled through a low-resistance Pari filter (no PEP). Afterwards, they underwent gamma-camera lung imaging. Images were analyzed for lung deposition fraction, expressed as a percent of the initial nebulizer activity, and deposition pattern, expressed in terms of inner-outer and apical-basal ratios. RESULTS: Lung deposition fraction was significantly lower with the Pari PEP device; the mean + SD deposition fraction was 6.10 + 3.05% (median 6.20%) with PEP, compared to 10.76 + 4.52% (median 10.32%) (p = 0.0078) without PEP. The inner-outer ratio was 2.01 + 0.69 (median 2.23) with PEP, which was significantly lower than without PEP (2.76 + 1.33, median 2.55) (p = 0.004). The apical-basal ratio was 0.82 + 0.31 (median 0.80) with PEP, which was not significantly different from no PEP (1.00 + 0.49, median 0.90). CONCLUSION: These results indicate that less aerosol is deposited in the lungs of patients with cystic fibrosis when the Pari LC Plus nebulizer is used with the Pari PEP device, as described in these experiments. Nevertheless, aerosol administration with this nebulizer and PEP device also results in a proportional redistribution of aerosol to the peripheral airways, compared to nebulization without the PEP device. The clinical relevance of this subtle redistribution of aerosol in cystic fibrosis patients will probably depend on the drug administered and disease severity.

Administration, Inhalation↗
PubMed1987

Use of ultrafast computed tomography to quantitate regional myocardial perfusion: a preliminary report.

The purpose of this study was to assess the potential for rapid acquisition computed axial tomography (Imatron C-100) to quantify regional myocardial perfusion. Myocardial and left ventricular cavity contrast clearance curves were constructed after injecting nonionic contrast (1 ml/kg over 2 to 3 seconds) into the inferior vena cava of six anesthetized, closed chest dogs (n = 14). Independent myocardial perfusion measurements were obtained by coincident injection of radiolabeled microspheres into the left atrium during control, intermediate and maximal myocardial vasodilation with adenosine (0.5 to 1.0 mg/kg per min, intravenously, respectively). At each flow state, 40 serial short-axis scans of the left ventricle were taken near end-diastole at the midpapillary muscle level. Contrast clearance curves were generated and analyzed from the left ventricular cavity and posterior papillary muscle regions after excluding contrast recirculation and minimizing partial volume effects. The area under the curve (gamma variate function) was determined for a region of interest placed within the left ventricular cavity. Characteristics of contrast clearance data from the posterior papillary muscle region that were evaluated included the peak myocardial opacification, area under the contrast clearance curve and a contrast clearance time defined by the full width/half maximal extent of the clearance curve. Myocardial perfusion (microspheres) ranged from 35 to 450 ml/100 g per min (mean 167 +/- 125). Two flow algorithms derived from characteristics of the contrast clearance curves showed a good correlation with regional myocardial flow determined by microspheres: the ratio of the peak myocardial opacification from baseline to the area under the left ventricular cavity curve (r = 0.7, p less than 0.001, SEE = 44.4 ml/min), and the ratio of the left ventricular cavity to posterior papillary muscle curve areas divided by the full width/half maximal contrast transit time in the region of the posterior papillary muscle (r = 0.82, p less than 0.001, SEE = 52.2 ml/100 g per min). The form of these two flow algorithms was derived from classical indicator dilution theory. In conclusion, indices derived from these data correlated well with regional myocardial perfusion in the posterior papillary muscle region of the dog as assessed by microspheres. This approach offers promise for the quantitation of regional myocardial perfusion and myocardial flow reserve in patients.

Algorithms↗
PubMed2002

Long-term functional outcome of kidneys in children with urolithiasis after ESWL treatment.

The aim of this study was to determine the long-term functional outcome of kidneys in children with urolithiasis treated by means of extracorporeal shock wave lithotripsy (ESWL). The effectiveness and safety of this method in the management of pediatric urinary stone disease was also studied. This prospective study enrolled 84 children, 33 boys (age: 9.1 +/- 3.8 yrs) and 51 girls (age: 9.6 +/- 3.9 yrs), with urolithiasis who were treated using a second-generation "Siemens" Lithostar lithotriptor, in the period between 1988 and 1998. Dynamic kidney scintigraphy using (99 m)Tc-DTPA was done prior to, immediately following ESWL treatment, three months later, and again after an observation period of 12 - 67 months (38 +/- 13 months). Immediate fragmentation rate was 90 %, while the calculus clearance rate was 61 %. Glomerular filtration rate (GFR), measured by clearance of (99 m)Tc-DTPA, immediately after an ESWL treatment of 107 +/- 6 ml/min was significantly lower compared to the pretreatment value of 118 +/- 7 ml/min, but returned three months later to 121 +/- 6 ml/min, and to 131 +/- 10 ml/min at the end of the observation period. A separate analysis was performed on three groups of patients treated by ESWL: with acute calculous disease, chronic calculous disease, and chronic calculous with partial stasis. ESWL treatment in children with acute obstruction was associated with an immediate increase in GFR; however, in chronic calculous disease a decrease in GFR was found. A return of GFR to the pretreatment level was observed at the three-month control in these patients. In patients with acute stone obstruction, at 3 and 12 - 67 months after ESWL treatment, GFR of the treated kidney was found to be significantly increased compared to the pretreatment level. In contrast, in children with chronic calculous disease this increase was modest. This study has demonstrated ESWL to be an effective treatment option for urinary calculi management, which can be safely performed in a pediatric population without long-term effects on the growing kidneys.

Acute Disease↗
PubMed1999

Evaluation of flow characteristics of soft-tissue vascular malformations using technetium-99m labelled red blood cells.

The estimation of intralesional haemodynamics is crucial in determining appropriate treatment for soft-tissue vascular malformations. The aim of this study was to develop a method to evaluate the flow characteristics of soft-tissue vascular malformations using technetium-99m labelled red blood cells (99mTc-RBCs). Seventy-nine soft-tissue vascular malformations, including 20 arteriovenous malformations and 59 venous malformations, in 57 patients were examined. Following the intravenous injection of 99mTc-RBCs, dynamic imaging was performed for 30 min with the lesion in the field of view (99mTc-RBC flow study). A time-activity curve was generated for the lesion, and the lesion was categorized as a high-flow or low-flow lesion by visual inspection of the curve. In low-flow lesions, mean vascular transit time (MTT) was calculated by curve fitting based on a two-compartment model. Twenty-nine lesions in 19 patients were examined twice, and reproducibility was assessed. In 23 venous malformations in 16 patients, 99mTc-Sn colloid was percutaneously injected into the intravascular space of the lesion, and dynamic data of 5-min duration were acquired (direct puncture scintigraphy). MTT was estimated from the washout curve and compared with MTT estimated by 99mTc-RBC flow study. 99mTc-RBC flow study classified all 20 arteriovenous malformations as high-flow lesions and all 59 venous malformations as low-flow lesions. In the low-flow lesions, MTT estimated by 99mTc-RBC flow study ranged from 61.2 to 2174.9 s. In the reproducibility study, complete concordance in classification and high correlation in MTT were shown between the first and second examinations. MTT estimated by 99mTc-RBC flow study was significantly correlated with that estimated by direct puncture scintigraphy. In summary, 99mTc-RBC flow study provides a quantitative indicator of intralesional haemodynamics in low-flow lesions in addition to accurate distinction between high-flow and low-flow lesions. The results of this study suggest the feasibility of detailed evaluation of flow characteristics in soft-tissue vascular malformations using 99mTc-RBCs.

Adolescent↗
PubMed2001

Respiratory deposition patterns of salbutamol pMDI with CFC and HFA-134a formulations in a human airway replica.

This paper describes a technique that uses a well-defined human airway replica and gamma counting as a standard method for evaluating and comparing the performance of medical inhalers and spacers. High-fidelity replicas reproduced as needed from master casts made from human cadavers include the oropharyngeal cavity, larynx, trachea, and five to nine generations of bronchi. Deposition in the small airways and alveoli region of the cast is simulated by material that passes through the upstream airways and is collected on foam filters. Deposition patterns in the respiratory tract replica were obtained by using radiolabel in the medical inhaler and by gamma scintigraphy. This technique was used to determine respiratory deposition patterns of salbutamol in a pressurized metered dose inhaler (pMDI) with chlorofluorocarbon (CFC, in-house formulation) and HFA-134 formulations (Proventil hydrofluoroalkane [HFA]). At an inspiration flow of 30 L/min, patterns in the salbutamol/CFC formula showed a high deposition in the oropharyngeal airway (78%) and a 16% deposition in the lung, similar to in vivo measurements reported in the literature. However, the salbutamol/HFA formula showed lower oral deposition (56%) but higher lung deposition (24%). The difference in the oral deposition patterns may be attributed to lower initial spray velocity, initial droplet evaporation rate, and possibly initial droplet sizes of Proventil HFA. The small orifice diameter (0.25 mm) of the Proventil HFA actuator produced a softer plume with a smaller impact force, resulting in lower oropharyngeal deposition. Cascade impactor measurements showed similar aerodynamic particle size distribution of the CFC and HFA formulations. We also showed that using spacers in the Proventil HFA resulted in a lower oropharyngeal deposition and higher lung deposition, indicating beneficial effects. Comparison of oropharyngeal deposition and those predicted by artificial throats used in the impactor measurements showed that, in general, the artificial throat predicted a lower deposition.

Administration, Inhalation↗
PubMed1999

Intravenous administration of superoxide dismutase entrapped in long circulating liposomes. II. In vivo fate in a rat model of adjuvant arthritis.

Rheumatoid arthritis (RA) is a prevalent and debilitating autoimmune disease that affects the joints. RA is characterized by an infiltration of the affected joint by blood-derived cells. In response to activation, these cells generate reactive oxygen species, resulting in an oxidative stress situation. One approach to counteract this oxidative stress situation is the use of antioxidants as therapeutic agents. The free radical scavenger enzyme superoxide dismutase (SOD) may be used as a therapeutic agent in rheumatoid arthritis, but its rapid elimination from the circulation is a major limitation. Targeted delivery of SOD may overcome this limitation. In this study, the utility of PEGylated liposomes (PEG-liposomes) for targeting SOD to arthritic sites was explored. The targeting of SOD to arthritic sites following intravenous administration of both PEG-liposomes and positively charged liposomes lacking PEG but containing stearylamine (SA-liposomes) in rats with adjuvant arthritis was studied. At 24 h post injection, the blood levels of long circulating liposomes with a mean size of 0.11 micrometer and 0.20 micrometer were 8- and 3-fold higher, respectively, as compared to the SA-liposomes. The majority of SOD administered in liposomal form remains within the liposomes when they circulate in the bloodstream. The highest target uptake was observed with PEG-liposomes with a mean size of 0.11 micrometer and the lowest uptake with the SA-liposomes. These results demonstrate that SOD can be targeted to inflamed sites most efficiently via small-sized PEG-liposomes. Small-sized PEG-coated liposomes are to be preferred if prolonged circulation and enhanced localization of SOD at arthritic sites are desired.

Animals↗
PubMed1986

Rubidium-82 kinetics after coronary occlusion: temporal relation of net myocardial accumulation and viability in open-chested dogs.

Serial assessment of perfusion and viability during myocardial infarction has not been feasible, in part, because of the long half-lives of available tracers. Rubidium-82 (82Rb) is a generator-produced, positron-emitting potassium analog with a short half-life (75 sec) that permits repeated studies. To determine the temporal relation of net myocardial 82Rb accumulation to loss of viability during prolonged ischemia, a 2-3 mCi bolus of 82Rb was given to 46 open-chested dogs while regional myocardial time-activity curves were obtained with beta probes at baseline, and serially after coronary occlusion lasting 1-6 hr. Hearts were then stained with triphenyl tetrazolium chloride (TTC) to assess the viability of the epicardium under the probe to a depth corresponding to the range of positrons. Irreversible injury occurred in two out of 16 experiments at 1 hr and ten out of 15 experiments at 3 hr and also at 6 hr (p less than 0.05 vs. 1 hr). In viable myocardial samples, rubidium extraction increased with low flow as compared with nonischemic controls for all time periods but was unchanged (failed to increase) in nonviable tissue. Net 82Rb accumulation decreased during 1 to 6 hr of occlusion in irreversibly injured samples (0.28 +/- 0.19 to 0.16 +/- 0.07, p less than 0.05) but remained unchanged in myocardial tissue subsequently shown to be viable. For myocardial samples that were nonviable at 3 and 6 hr, changes in net accumulation of tracer became abnormal only after 6 hr of occlusion. The mechanisms primarily responsible for the decrease in net accumulation of 82Rb at 6 hr appeared to be leakage of tracer after first pass. Therefore, failure to increase extraction at low flows may be an early indicator of cell death, whereas membrane leakage occurs several hours after loss of viability.

Animals↗
PubMed1998

Increased affinity leads to improved selective tumor delivery of single-chain Fv antibodies.

Mr 25,000 single-chain Fv (scFv) molecules are rapidly eliminated from the circulation of immunodeficient mice, yielding highly specific retention of small quantities of scFv in human tumor xenografts. We postulated that the specific retention of scFv in tumor could be enhanced by engineering significant increases in the affinity of the scFv for its target antigens. Affinity mutants of the human anti-HER2/neu (c-erbB-2) scFv C6.5 were generated by site-directed mutagenesis, which target the same antigenic epitope with a 320-fold range in affinity (3.2 x 10(-7) to 1.0 x 10(-9) M). In vitro, the Kd of each scFv correlated closely with the duration of its retention on the surface of human ovarian carcinoma SK-OV-3 cells overexpressing HER2/neu. In biodistribution studies performed in scid mice bearing established SK-OV-3 tumors, the degree and specificity of tumor localization increased significantly with increasing affinity. At 24 h after injection, tumor retention of the highest affinity scFv was 7-fold greater than that of a mutant with 320-fold lower affinity for HER2/neu. Because the rapid renal clearance of scFv may blunt the impact of improved affinity on tumor targeting, the distributions were also assayed in the absence of renal clearance (e.g., in mice rendered surgically anephric). In this model, the peak tumor retentions of the two higher affinity scFv approximated that reported previously for IgG targeting the same SK-OV-3 tumors in scid mice with intact kidneys. In contrast, the mutant with the lowest affinity for HER2/neu failed to accumulate in tumor, indicating the presence of an affinity threshold that must be exceeded for active in vivo tumor uptake. These results indicate that affinity can significantly impact the in vivo tumor-specific retention of scFv molecules.

Adenocarcinoma↗
PubMed1996

Defibrillation shocks over epicardial patches produce sympathetic neural dysfunction in man.

INTRODUCTION: The purpose of this study was to determine the effect of direct current (DC) shocks on cardiac sympathetic innervation in humans using I-123-metaiodobenzylguanidine (MIBG) scintigraphy. Decreased efferent sympathetic neural function has been demonstrated following > 10-J DC shocks delivered through epicardial patch electrodes in dogs. To evaluate the effect of DC shocks on cardiac sympathetic innervation in humans, we performed MIBG scintigraphy in 11 patients (ages 46 to 75 years) prior to and after receiving shocks from an implantable cardioverter defibrillator (ICD). METHODS AND RESULTS: This study was performed during an ICD generator change in 7 patients with epicardial patch electrodes and at the time of initial ICD implantation in 4 patients: 2 with epicardial patch electrodes, and 2 with a transvenous ICD system. All patients had spontaneous and inducible ventricular tachycardia. Prior to ICD implantation and remote from any cardioversions or shocks, baseline MIBG and thallium-201 scintigraphy were performed. Repeat MIBG scintigraphy was performed after delivery of ICD shocks and compared with the baseline scans to determine the effect of the shock on sympathetic neural function. The baseline scans revealed focal areas of reduced MIBG uptake in areas of thallium perfusion defects in all patients except the patient without structural heart disease whose scans were normal. Postshock, patients with epicardial patch electrodes who received at least one 24-J shock and had the postshock MIBG scan performed within 4 hours demonstrated no cardiac uptake of MIBG. Two patients with epicardial patch electrodes had no change in the postshock MIBG scans: 1 had a maximal shock of 20 J, and the other had the postshock scan delayed for 11 hours. The 2 patients with a transvenous lead system demonstrated no change in the postshock MIBG scan when compared with baseline. CONCLUSIONS: This study demonstrates that following DC shocks delivered over epicardial patch electrodes, there is diffuse reduction in MIBG uptake that probably represents cardiac sympathetic neural dysfunction that appears to be transient. Sympathetic function does not appear to be affected by shocks delivered over a transvenous lead system.

3-Iodobenzylguanidine↗
PubMed2003

Effect of inhalation of salbutamol, beclomethasone dipropionate & ipratropium bromide on mucociliary clearance in some patients with chronic stable bronchial asthma.

BACKGROUND & OBJECTIVES: Asthma is now regarded as an inflammatory disease and bronchial inflammation may disrupt mucociliary function. Inhaled drugs may act by improving mucociliary function. The aim of the study was to investigate the effect of salbutamol, ipratropium bromide and beclomethasone on mucociliary clearance in patients with chronic stable asthma and to compare the efficacy of these drugs on mucociliary clearance. METHODS: Ten patients with chronic stable asthma were enrolled in the study, but two patients did not complete the study. Patients with bronchial asthma were chosen on clinical grounds. (99m)Tc phytate radioaerosol generated through a nebulizer, was given to each patient on four days. After each administration the radioactivity over the thorax was constantly measured in sequential frame mode for 120 min. Radioactivity in the thorax was also measured after 24 h. A base-line pulmonary function test with reversibility was obtained. Salbutamol, ipratropium bromide, beclomethasone dipropionate and placebo inhalation were given randomly to each patient on four days. RESULTS: The mean age of patients (n = 8) was 36 +/- 9.3 yr and mean duration of symptoms was 5 +/- 6.6 yr. There was no visual impression that mucociliary clearance was enhanced with any of the drugs. The time activity curves did not show any visually recognisable change in slope. In only one patient the curve tended to show a steeper slope with ipratropium inhalation. In the rest of the patients the curves showed no difference at all with medication when compared with placebo. All the quantitative indices analyzed by two-way ANOVA at the end of one and two hours were comparable for the three test drugs and placebo. None of the three test drugs demonstrated statistically significant mucociliary clearance effect compared with placebo. However, the temporal difference in airways clearance efficiency (ACE) was significant with beclomethasone and ipratropium bromide. INTERPRETATION & CONCLUSION: Inhalation of any of the three drugs tested did not produce any immediate improvement in mucociliary clearance as compared to placebo in patients with stable bronchial asthma suggesting the need for further studies using higher doses of drugs for longer duration in a large sample.

Administration, Inhalation↗
PubMed1995

Improved tumor radioimmunodetection using a single-chain Fv and gamma-interferon: potential clinical applications for radioimmunoguided surgery and gamma scanning.

Previous studies have shown that (a) single-chain antibody binding proteins, or sFvs, localize experimental tumor xenografts (D.E. Milenic et al, Cancer Res., 51: 6363-6371, 1991) and (b) the administration of gamma-interferon (IFN-gamma) increases the expression of a high molecular weight glycoprotein, tumor-associated glycoprotein 72 (TAG-72), which improves mAb-based tumor targeting as well as radioimmunotherapy (J. W. Greiner et al., Cancer Res., 53: 600-608, 1993). The present experimental study was designed to determine whether exploiting those two observations in combination could augment tumor detection. Initial results revealed significant localization of a single-chain antibody binding protein of CC49 (i.e., CC49 sFv), a second generation anti-TAG-72 mAb, to human colon tumor xenografts (HT-29), which express low constitutive TAG-72 levels. IFN-gamma treatment of mice bearing HT-29 tumors significantly increased TAG-72 levels in the tumor xenografts. Increased TAG-72 expression was accompanied by a 2-4-fold augmentation of CC49 sFv localized to the HT-29 tumors, measured by direct quantitation of 125I-labeled CC49 sFv tumor deposition as well as tumor:normal tissue ratios. Enhanced CC49 sFv tumor localization improved HT-29 tumor visualization by external scintigraphy as well as when using a hand-held gamma-detecting probe to discriminate between normal (i.e., heart, hind leg) and tumor tissue. The gamma-detecting probe was the same as that used intraoperatively with 125I-labeled CC49 IgG to identify occult tumors in patients. The present experimental findings indicate that the efficiency by which 125I-labeled CC49 sFv localizes tumor in vivo can be enhanced with IFN-gamma. Results of the present study suggest that (a) the incorporation of an IFN-gamma treatment schema prior to radioimmunscintigraphy may increase the signal from the tumor site(s), thus providing a better discrimination between tumor and background, and (b) combining 125I-labeled CC49 sFv with IFN-gamma will not only reduce the time interval between antibody injection and surgery, but will also increase the efficiency of tumor localization using the intraoperative gamma-detecting probe.

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